J Neural Transm (2006) 113: 1625–1644
DOI 10.1007/s00702-006-0579-2
Review
The significance of the cholinergic system in the brain
during aging and in Alzheimer’s disease
R. Schliebs, T. Arendt
Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany
Received: September 11, 2006 = Accepted: September 27, 2006 = published online October 13, 2006
# Springer-Verlag 2006
Summary Acetylcholine is widely distributed in the nervous system and
has been implicated to play a critical role in cerebral cortical develop-
ment, cortical activity, controlling cerebral blood flow and sleep-wake
cycle as well as in modulating cognitive performances and learning and
memory processes. Cholinergic neurons of the basal forebrain complex
have been described to undergo moderate degenerative changes during
aging, resulting in cholinergic hypofunction that has been related to the
progressing memory deficits with aging. Basal forebrain cholinergic cell
loss is also a consistent feature of Alzheimer’s disease, which has been
suggested to cause, at least partly, the cognitive deficits observed, and
has led to the formulation of the cholinergic hypotheses of geriatric
memory dysfunction. Impaired cortical cholinergic neurotransmission
may also contribute to b-amyloid plaque pathology and increase phos-
phorylation of tau protein the main component of neurofibrillar tangles
in Alzheimer’s disease. Understanding the molecular mechanisms under-
lying the interrelationship between cortical cholinergic dysfunction,
b-amyloid formation and deposition, and tau pathology in Alzheimer’s
disease, would allow to derive potential treatment strategies to pharma-
cologically intervene in the disease-causing signaling cascade.
Keywords: Alzheimer, cholinergic system, beta-amyloid, tau, nerve
growth factor
Brain cholinergic system, cognition
and dementing disorders
Central cholinergic system
Central cholinergic neurons can be subdivided into projec-
tion neurons located mainly in the forebrain and upper brain
stem, and interneurons present in the caudate-putamen,
nucleus accumbens, hippocampus, cerebral cortex, hypo-
Correspondence: Dr. Reinhard Schliebs, Department of Neurochemistry,
Paul Flechsig Institute for Brain Research, University of Leipzig, Jahnallee
59, 04109 Leipzig, Germany
e-mail: schre@medizin.uni-leipzig.de
thalamus and spinal cord. Moreover, cholinergic projection
neurons comprise also motor neurons in the spinal cord
(cranial nerves 3–7, and 9–12) as well as cholinergic neu-
rons in the sympathic and parasympathic nervous system
(see e.g., Martinez-Murillo and Rodrigo, 1995).
The cholinergic neurons in the basal forebrain and in the
pontine reticular formation are forming parts of the ascend-
ing reticular activating system. The basal forebrain cholin-
ergic complex comprising medial septum, horizontal and
vertical diagonal band of Broca, and nucleus basalis of
Meynert provides the mayor cholinergic projections to the
cerebral cortex and hippocampus, while the pontine cholin-
ergic system acts mainly through thalamic intralaminar
nuclei and provides only a minor innervation of the cortex.
In particular, neurons located in the medial septum inner-
vate predominantly the hippocampus, while those of the
vertical and horizontal diagonal band project to the anterior
cingulate cortex and olfactory bulb, respectively. Choliner-
gic neurons of the nucleus basalis of Meynert provide effer-
ents to the amygdala and throughout the rest of the cortical
mantle (Bigl et al., 1990; Fig. 1). They display a continuum
of large cells that express nerve growth factor (NGF) and
its cognate receptors, calbindin, and glutamate receptors.
Intermingled with these cholinergic cells are smaller in-
terneurons containing NADPH-diaphorase, GABA, calcium
binding proteins and several inhibitory neuropeptides in-
cluding galanin (Mufson et al., 2003). The GABAergic neu-
rons within the basal forebrain system act as interneurons
that make connections with cholinergic neurons (Frotscher,
1992) or may project to the hippocampus (Toth et al.,
1993).
1626
Fig. 1. Cholinergic innervation of the cortical mantle. The basal forebrain
cholinergic complex comprising medial septum, horizontal and vertical
diagonal band of Broca, and nucleus basalis of Meynert provides the
mayor cholinergic projections to the cerebral cortex and hippocampus.
Neurons located in the medial septum innervate predominantly the
hippocampus, while those of the vertical and horizontal diagonal band
project to the anterior cingulate cortex and olfactory bulb (limbic cortex),
respectively. Cholinergic neurons of the nucleus basalis of Meynert
provide efferents to the amygdala and throughout the rest of the cortical
mantle. Individual cells in the nucleus basalis=diagonal band complex
have a restricted axonal projections to the cerebral cortex in the rat.
Although the projection as a whole is very widespread, the projection of
individual cells is limited to a very restricted area within the cortex, not
more than 1–2 mm in diameter (modified according to Arendt, 1999)
Physiologically, the brain cholinergic system plays a role
in controlling cerebral blood flow (Biesold et al., 1989;
Barbelivien et al., 1999; Sato et al., 2004), cortical activity
(Detari et al., 1999; Lucas-Meunier et al., 2003), and sleep-
wake cycle (Lee et al., 2005) as well as in modulating
cognitive function and cortical plasticity (Arendt and Bigl,
1986; Bigl and Schliebs, 1998; Schliebs and Bigl, 1996;
Schliebs et al., 1996, for review, see e.g. McKinney, 2005).
Central cholinergic function in learning and memory
Already for a long time it is known that agents such as
tropan alkaloids that are today known to block muscarinic
cholinergic receptor sites, result in memory deficits and
cognitive disturbancies. The involvement of central cholin-
ergic function in learning and memory was first postulated
by Deutsch (1971), and later further corroborated by phar-
macological studies (Drachman and Leavitt, 1974) demon-
strating that centrally acting anticholinergic drugs impaired
cognitive performance in young healthy patients to a level
detectable in dementing disorders, while enhancement of
central cholinergic function improved the performance of
aged patients (Drachman, 1977).
A vast number of experimental studies then has con-
firmed that defined administrations of anticholinergic drugs
R. Schliebs, T. Arendt
produce dose-dependent deleterious effects on cognitive
performance of a broad spectrum of learned behaviour in
rats (Fibiger, 1991; Fr€olich et al., 1989) as well as in
humans (Christensen et al., 1992; Molchan et al., 1992),
providing evidence for the important role of the central
cholinergic system in realizing cognitive processes. Cholin-
ergic lesions by electrolytic or excitotoxic methods as well
as application of the cholinergic immunolesion strategy
(Wiley et al., 1991) that produces a more specific and
selective destruction of basal forebrain cholinergic cells
(Roßner et al., 1995; Heckers et al., 1994; reviewed in
Schliebs, 2005a), and stimulation of basal forebrain choli-
nergic cells provided experimental tools to further empha-
size this view. Behavioral studies on such animal models
demonstrated that lesion-induced damage to basal forebrain
cholinergic system, and their cholinergic projections to the
neocortex induced deficits related to cognitive impairments,
especially on attentional processes (Sarter and Bruno, 1997),
as well as on learning and memory processes (Dunnett and
Fibiger, 1993; Everitt and Robbins, 1997; Wenk, 1993;
Woolf, 1997; for review, see also, McKinney, 2005).
Cholinergic system in postnatal development and aging
A number of anatomical, electrophysiological, chemical,
and behavioral studies have highlighted also a critical role
for acetylcholine in cortical development, and its impor-
tance in establishing synaptic contacts in networks of cells
that will subserve complex cognitive functions in adult-
hood (see e.g., Berger-Sweeney, 2003). There is ample evi-
dence that acetylcholine plays a role in structural and
functional remodeling of cortical circuits. In particular,
the involvement of acetylcholine in visual cortex plasticity
has extensively been investigated over the years (Roßner
et al., 1994; Schliebs et al., 1982; Walch et al., 1989; for
review, see e.g., Gu, 2003).
The occurance of abnormalities in the control of cortical
cholinergic input very early in life such as disruption of
trophic factor support (Mufson et al., 2002; Ginsberg et al.,
2006b), has been assumed to mediate early-life cognitive
limitation, a disease stage that is suggested to subsequent-
ly develop into mild cognitive impairment (MCI; Sarter
and Bruno, 2004) and Alzheimer disease. Enhancement of
cholinergic neurotransmission in subjects with MCI who
demonstrate an increased risk of developing Alzheimer’s
disease, has been shown to specifically improve hippocam-
pal function, thus further supporting the suggestion that
cholinergic deficits in MCI are functionally relevant (Gron
et al., 2006), but may appear to be modified by compensa-
tory neurochemical mechanisms in the cholinergic system
Cholinergic transmission and Alzheimer’s disease
(DeKosky et al., 2002). Cholinergic challenges in Alzheimer
patients and in subjects with MCI differentially affected
hippocampal activation as revealed by functional magnetic
resonance imaging (MRI). These data support the sug-
gestion of a key role of the cholinergic system in the func-
tional processes that lead to Alzheimer’s disease (Goekoop
et al., 2006).
Cholinergic dysfunction in Alzheimer’s disease
In late 1970s several groups provided evidence of severe
deficiency of presynaptic cholinergic markers in the ce-
rebral cortex of patients with early-onset of Alzheimer’s
disease (Davies and Malloney, 1976; Bowen et al., 1976;
Perry et al., 1977a, b; see also Bigl et al., 1990). The cor-
relation of clinical dementia ratings with the reductions in
a number of cortical cholinergic markers such as choline
acetyltransferase, muscarinic and nicotinic acetylcholine
receptor binding as well as levels of acetylcholine (Bierer
et al., 1995; Fr€
olich and Riederer, 1992; Gsell et al., 1993,
1997, 2004; Moll et al., 1990; Nordberg, 1992; Sofic et al.,
1989), suggested an association of cholinergic hypofunc-
tion with cognitive deficits, which led to the formulation of
the cholinergic hypothesis of memory dysfunction in senes-
cence and in Alzheimer’s disease (see, Bartus, 2000). This
is further supported by in vivo measurements of choliner-
gic receptor expression by positron emission tomography
(PET) at different stages of Alzheimer’s disease demon-
strating receptor abnormalities that change with disease
1627
progression (Nordberg, 2001). While there is no doubt that
severe loss of cortical cholinergic innervation exists already
in the initial stages of presenile (early onset) as well as in
the advanced stages of late-onset Alzheimer’s disease, the
assumption of cholinergic denervation being an early and
initial stage also in mild, late-onset Alzheimer’s disease has
been debated (for review and references, see Mesulam,
2004). The cholinergic changes in late-onset Alzheimer’s
disease should also be considered in the light of normal
age-related decline in cholinergic function. During aging
cholinergic neurons of the basal forebrain complex, have
been described to undergo moderate degenerative changes,
including cell atrophy, downregulation of choline acetyl-
transferase (ChAT) activity, and mild cell loss detectable in
both animals and humans, resulting in cholinergic hypo-
function that has been related to the progressing memory
deficits with aging (Bigl et al., 1990; Wenk, 1993; Arendt
et al., 1987). A correlation of the loss of cholinergic neu-
rons of the basal forebrain and the extent of cognitive distur-
bance as assessed by scoring the Mini mental state (MMS)
in both healthy individuals and a number of various demen-
ting disorders, revealed that cognitive deficits are detect-
able not earlier before at least 30% of the total cholinergic
basal forebrain cells have degenerated (Fig. 2). This indi-
cates a high capacity of the basal forebrain cholinergic
system with regard to respond to neuronal degeneration.
Degeneration of basal forebrain cholinergic cells has
also been observed in a number of other dementing disor-
ders (Table 1), such as Parkinsons’s disease (Arendt et al.,
Fig. 2. Correlation of the loss of cholinergic
neurons of the basal forebrain and the extent
of cognitive disturbance as assessed by scor-
ing the Mini mental state (MMS). This rela-
tionship is independent of the genesis of the
neurodegeneration. Healthy individuals dis-
play MMS scores of around 30, while
MMS scores of 24 or lower are considered
to represent a dementing state. In order to
reach a MMS score of 24, a loss of choliner-
gic neurons by about of 30% is required,
indicating a high capacity of the cholinergic
system to respond to neurodegenerative pro-
cesses (modified according to Arendt, 1999)
1628
Table 1. Disorders with cognitive deficits which are accompanied by
cholinergic neuronal cell loss in the nucleus basalis Meynert
Alzheimer’s disease
Parkinson’s disease
Parkinsonism with dementing complex of Guam
Striatonigral degeneration
Down syndrome
Dementia pugilistica
Pick’s disease
Wernicke-Korsakoff syndrome
Presenile argyrophilic subcortical dystrophy
progressive supranuclear palsy
Jakob-Creutzfeld disease
Olivo-ponto cerebellar atrophy
subacute sklerotic panencephalitis
traumatic brain injury (boxing syndrome)
1983; Jellinger, 1991, 2000; Whitehouse et al., 1983),
Down-syndrome, progressive supranuclear palsy, Jakob-
Creutzfeld disease (Arendt et al., 1984b), Korsakoff’s syn-
drome (Bohnen et al., 2003; Terry and Buccafusco, 2003) as
well as after chronic ethanol intake (Arendt, 1994), and
traumatic brain injury (Salmond et al., 2005). However, in
contrast to many other dementing disorders, in Alzheimer’s
disease the cholinergic dysfunctions are accompanied by the
occurance of two major histopathological hallmarks such as
b-amyloid plaques deposed extracellularly in cerebral corti-
cal and hippocampal areas and neurofibrillary tangles that
occupy much of the cytoplasm of select cortical pyramidal
neurons. Despite a considerable progress in understanding
the biochemical processes of formation and deposition of
b-amyloid peptides in Alzheimer’s disease, the molecular
mechanisms of what causes the specific degeneration of
basal forebrain cholinergic cells is still a matter of debate.
But during the last decade increasing evidence has accumu-
lated suggesting an interrelationship between basal forebrain
cholinergic neurotransmission, neurotrophin signaling, and
metabolism of the amyloid precursor protein (APP), which
will be highlighted in the next chapters.
Cholinergic control of amyloid precursor
protein processing
The major constituent of the neuritic plaques is the 4 kDa
b-amyloid peptide that is derived from a much larger amyloid
precursor protein (APP) by the sequential action of b- and
g-secretases. Alternatively, the non-amyloidogenic secretory
pathway of APP processing includes the proteolytic cleavage
of APP by the a-secretase between amino acid position 16
and 17 of the b-amyloid domain that results into the secretion
of sAPPa and precludes the generation of b-amyloid (for
review on APP processing, see e.g. Selkoe, 2003).
R. Schliebs, T. Arendt
First evidence of a link between cholinergic dysfunction
and APP processing was provided by observations of a co-
localization of acetylcholinesterase (AChE) with b-amy-
loid deposits in Alzheimer brains (Mesulam, 1986; Moran
et al., 1993), which was further validated by in vitro studies
(Nitsch et al., 1992). Secretion of sAPPa was enhanced by
electrical stimulation of tissue slices from rat brain, which
could be blocked by the sodium-channel antagonist tetro-
dotoxin (Nitsch et al., 1993). Selective activation of M1=
M3-but not M2=M4-mAChR increased sAPPa secretion
and decreased total b-amyloid formation both in vitro
(Ensinger et al., 1993: Farber et al., 1995; Walland et al.,
1997; M€uller et al., 1997) and in vivo in patients with
Alzheimer’s disease (Hock et al., 2003; Nitsch et al., 2003).
A similar effect could be achieved by direct activation of
protein kinase C (PKC) by phorbol ester indicating that
mAChR mediate their effects on APP processing through
activation of the phosphatidyl inositol signaling pathway
(Hung et al., 1993). However, inhibition of sAPPa in the
presence of PKC inhibitors was not complete (Slack et al.,
1995), indicating that other pathways downstream of the
acetylcholine receptor including tyrosine kinase (Slack et al.,
1995) or MAP kinase (Haring et al., 1998; Slack, 2000)
may also be involved in the control of APP processing.
Moreover, inhibitors of AChE were found to increase se-
cretion of sAPPa in both cortical rat brain slices (Mori
et al., 1995) and cell culture (Racchi et al., 2001). Selective
lesion of basal forebrain cholinergic cells in rat brain
(Roßner et al., 1998a; Lin et al., 1999), or administration of
selective M1-muscarinic agonists to mice (Seo et al., 2002)
provided strong in vivo evidence that cortical APP proces-
sing is controlled by cholinergic activity originating from
the basal forebrain. Scopolamine treatment of transgenic
Tg2576 mice resulted in increased levels of fibrillar b-amy-
loid (1–40) and b-amyloid (1–42), and enhanced a-secre-
tase activity, suggesting that chronic suppression of cortical
muscarinic cholinergic transmission may alter the balance
between a- and b-secretory APP processing by favouring
the amyloidogenic route (Liskowsky and Schliebs, 2006).
The pathway by which mAChR regulate a-secretase-
mediated sAPPa release occurs via PKCa and Src-tyro-
sine kinase-dependent activation of ERK1=2 (Canet-Aviles
et al., 2002). Given that a-and b-secretory APP processing
are differentially regulated through mAChR subtypes, we
recently examined in SH-SY5Y neuroblastoma cells the sig-
naling pathways through which mAChR subtypes control
b-secretase activity (Z€uchner et al., 2004). The expres-
sion of the b-secretase BACE1 was found to be differen-
tially regulated in a subtype-specific manner by mAChR.
Agonist binding to M1=M3-receptors upregulated BACE1
Cholinergic transmission and Alzheimer’s disease
expression through activation of both protein kinase C and
MAP kinase signaling cascades. In contrast, BACE1 ex-
pression was downregulated by activation of M2-mAChR
and protein kinase A-mediated pathways (Z€ uchner et al.,
2004). These results may partly explain the observed dete-
riorations of Alzheimer’s disease patients after initial
improvements by AChE-inhibitor or M1-muscarinic ago-
nist treatment.
Nicotine through action on nicotinic nAChR has also
been observed to modulate APP processing both in cell
culture (Efthimiopoulos et al., 1996; Seo et al., 2001) and
in vivo (Utsuki et al., 2002) by favouring the non-amyloi-
dogenic pathway when treated with low doses of nicotine
(Lahiri et al., 2002). Moreover, inhibition of b-amyloid
fibril formation and disruption of preformed b-amyloid fi-
brils by nicotine was described (Salomon et al., 1996; Ono
et al., 2002). Chronic treatment of transgenic Tg2576 APP
mice with nicotine significantly reduced b-amyloid plaque
deposition as compared to non-treated controls (Nordberg
et al., 2002; Hellstrom-Lindahl et al., 2004) suggesting
beneficial effects of nicotine for Alzheimer’s disease pa-
tients. This is further emphasized by a recent study in
tobacco smoking elderly people who demonstrated less
b-amyloid deposition in the entorhinal cortex as compared
to non-smokers (Court et al., 2005).
Acetylcholinesterase and b-amyloid
Co-localization of acetylcholinesterase (AChE) with b-
amyloid deposits in Alzheimer brains (Mesulam, 1986;
Moran et al., 1993) as well as the capability of AChE to
affect APP processing (Lahiri et al., 1997; Mori et al., 1995;
Racchi et al., 2001), and aggregation of b-amyloid pep-
tides (Inestrosa et al., 1996) suggested a particular role of
the acetylcholine-degrading enzyme in the pathogenesis of
Alzheimer’s disease (see e.g., Zhang, 2004; Racchi and
Govoni, 2003).
AChE appears to promote the aggregation of b-amyloid
at least in vitro by forming a complex with the growing
b-amyloid fibrils (Alvarez et al., 1997; Bartolini et al.,
2003). This association of AChE with b-amyloid induces
alterations in some of the enzyme properties (pH sensitiv-
ity, substrate concentration) and increases the neurotoxic-
ity of Alzheimer fibrils (Alvarez et al., 1998; Reyes et al.,
2004), which correlates with corresponding findings in se-
nile plaques from Alzheimer brains (Geula and Mesulam,
1989; Schatz et al., 1990). A role of AChE in b-amyloid
plaque formation was also supported by in vivo studies. In
the neocortex of 18-month-old transgenic Tg2576 mice
that demonstrated a considerable b-amyloid burden, a
1629
strong staining for AChE activity was found throughout
the b-amyloid plaques accompanied by local distortions
of the cholinergic fiber network. The amyloid plaque core
was observed to be associated with intense AChE activity
and a weakly stained AChE-positive halo (Apelt et al., 2002).
In doubly transgenic mice overexpressing both human
AChE and the Swedish mutation of human APP acceler-
ated plaque formation as well as larger plaque size have
been observed, as compared to single transgenic APP mice
(Rees et al., 2003). These findings provide strong evidence
for an important role of AChE in amyloid deposition.
AChE interacts with b-amyloid by the peripheral anionic
binding site (PAS) of the enzyme (Inestrosa et al., 1996;
Inestrosa and Alarcon, 1998; Reyes et al., 1997), which led
to the suggestion that inhibition of the PAS of the AChE
may represent a potential strategy to intervene in b-amy-
loid formation (Fuentealba et al., 2004).
However, vice versa, there are also reports that b-amy-
loid increased AChE in both neuronally differentiated P19
cells and in primary murine cortical cells (Sberna et al.,
1997; Saez-Valero et al., 2003; Fodero et al., 2004), with
b-amyloid (1–42) being more potent than b-amyloid (1–40).
The b-amyloid (1–42)-induced enhancement of AChE was
found to be mediated through the action b-amyloid on a7
nicotinic acetylcholine receptors (nAChR), indicating that
the local increase in AChE around amyloid plaques in
Alzheimer’s disease may also be a result of a direct action
of b-amyloid on a7 nAChR located on terminals around
senile plaques (Fodero et al., 2004).
Butyrylcholinesterase and Alzheimer’s disease
Recent studies examining butyrylcholinesterase (BuChE)
in post mortem brain samples from dementia patients in re-
lationship to the progression of cognitive impairment sug-
gested an essential role of BuChE in disease progression.
Both BuChE and AChE appear to exert broader functions
in the central nervous system than previously thought,
which may also have consequences on treatment strategies
with cholinesterase inhibitors by selectively targeting AChE
and BuChE (Ballard et al., 2005; Lane et al., 2006; Tasker
et al., 2005; Darreh-Shori et al., 2006).
BuChE, the sister enzyme of AChE, is a serine hydrolase
that catalyses the hydrolysis of esters of choline, including
acetylcholine (Ballard et al., 2005; Darvesh et al., 2003),
but its role in the brain still needs to be elucidated. It
has been associated with cellular proliferation and neurite
growth during the development of the nervous system.
However, the viability of mice deficient of AChE but with
normal level of BuChE (Li et al., 2000; Mesulam et al.,
1630
2002a), suggests an essential function of BuChE in the
brain in overtaking some actions of the AChE and compen-
sating for the loss of AChE. This is further supported by its
widely distribution in the nervous system. The enzyme is
primarily expressed in neuronal somata and proximal den-
drites in the cerebral cortex, mainly in deeper layers, in the
hippocampal formation, amygdala, and in many thalamic
nuclei, while the AChE can be detected in somata and
axons (Darvesh et al., 1998; Darvesh and Hopkins, 2003).
Particularly, in the thalamus, BuChE and AChE-positive
neurons displayed both distinct and overlapping distribu-
tion patterns with some nuclei primarily expressing one
or the other cholinesterase (Darvesh and Hopkins, 2003).
AChE appears localized mainly in neurons, whereas BuChE
is primarily associated with glial cells, as well as with
endothelial cells and neurons (Ballard, 2002; Darvesh
et al., 2003).
It has been hypothesized that AChE and BuChE are co-
regulators of the duration of action of acetylcholine in
cholinergic neurotransmission (Darvesh et al., 1998; Xie
et al., 2000; Mesulam et al., 2002a, b). This suggestion is
further supported by the different kinetic properties of both
AChE and BuChE (Greig et al., 2005). BuChE is less effi-
cient in hydrolysing acetylcholine at low concentrations but
highly effective at high acetylcholine levels at which AChE
becomes subtrate inhibited (Kamal et al., 2006; Giacobini,
2003), indicating a supportive role of acetylcholine hydro-
lysis by BuChE under conditions of high brain activity.
The single gene on chromosome 3 that codes BuChE
displays polymorphisms, resulting in several enzymes with
different levels of activity, such as the atypical, the K- and
J-variants of BuChE (Bartels et al., 1992a, b). Moreover,
BuChE exists in several different molecular forms, includ-
ing monomers and oligomers that consist of identical cat-
alytic subunits (Darvesh et al., 2003).
In healthy human brain AChE predominates over BuChE
(Giacobini, 2003). However, in Alzheimer’s disease, in
contrast to AChE which is lost early during the course of
the disease (see above), BuChE levels, mainly the G1 form,
rise with disease progression (Perry et al., 1978; Arendt
et al., 1992). The ratio of BuChE to AChE increases strik-
ingly in cortical regions of Alzheimer patients (Arendt
et al., 1984a; Perry et al., 1978; Giacobini, 2003). BuChE
occurs in plaques, tangles, and amyloid-containing vessels
(Arendt et al., 1992; Geula et al., 1994), and the levels of
BuChE correlate positively with the development of amy-
loid plaques and neurofibrillar tangles in Alzheimer brains
(Geula et al., 1994; Geula and Mesulam, 1995; Guillozet
et al., 1997). The BuChE becomes associated with amyloid
plaques at approximately the same time that the b-amyloid
R. Schliebs, T. Arendt
deposit assumes a compact b-sheat conformation, suggest-
ing a role of BuChE in the transformation of b-amyloid
into neuritic plaques (Mesulam and Geula, 1994; Guillozet
et al., 1997). Indeed, selective inhibition of BuChE (cym-
serine analogs) in both SK-N-SH-neuroblastoma cells, rat
brain, and double transgenic mice (overexpressing human
APPswe and presenilin-1) resulted into elevated acetylcho-
line level, enhanced long-term potentiation and in
decreased b-amyloid level (Greig et al., 2005).
Moreover, BuChE has also been observed in both intra-
and extracellular neurofibrillary tangles, neurites associ-
ated with plaques and in neuropil threads (Perry et al.,
2003; Gomez-Ramos et al., 1994). Interestingly, studies in
autopsy-diagnosed dementia (Alzheimer’s disease and de-
mentia of Lewy bodies) demonstrated that patients with the
K-variant of BuChE have less severe phosphorylation of
tau in the temporal cortex (Ballard et al., 2005), which may
be of therapeutic relevance. The properties of cholines-
terases detected in plaques and tangles were similar to
those found in glial cells (Wright et al., 1993), suggesting
a glial source of plaque-associated BuChE.
Taken together, selective targeting of BuChE might be of
therapeutic value in Alzheimer’s disease (Darvesh et al.,
2003). However, a recent in vivo study failed to observe
increased synaptic BuChE activity in brain of Alzheimer
patients (Kuhl et al., 2006).
Toxicity of b-amyloid on the cholinergic system
It has been hypothesized that b-amyloid peptides induce
neurodegenerative changes at cholinergic terminals (Auld
et al., 2002; Selkoe, 2002; Dolezal and Kasparova, 2003;
Harkany et al., 2000; Yan and Feng, 2004). However, it is
still a matter of debate whether the loss and degeneration of
cholinergic terminals are primary events or secondary to
the b-amyloid plaque pathology. The most predominant
b-amyloid-peptides detected in Alzheimer plaques are b-
amyloid (1–40) and b-amyloid (1–42) (Masters et al., 1985;
Selkoe et al., 1986). b-amyloid (1–42) is more fibrillogenic
and displays higher neurotoxicity in vivo than b-amyloid
(1–40) (Klein et al., 1999). Both peptides are able to
form several aggregates with different physicochemical and
pharmacological properties: soluble, low-molecular weight
monomers (Taylor et al., 2003), oligomers and amyloid-
derived diffusible ligands (ADDLs), respectively (Lambert
et al., 1998; Kirkitadze et al., 2001; Walsh et al., 2002a;
Bitan et al., 2003; Chromy et al., 2003; Gong et al., 2003),
protofibrils (Harper et al., 1997; Walsh et al., 1999) in
equilibrium with insoluble, high-molecular weight fi-
brils (Teplow 1998; Walsh et al., 1999). The insoluble,
Cholinergic transmission and Alzheimer’s disease 1631

high-molecular weight fibrils are major components of the Modulatory role of b-amyloid on cholinergic function
senile plaques in the Alzheimer brain and are assumed to
b-amyloid is also produced under normal conditions and
be the most toxic forms responsible for cholinergic neuro-
secreted in the brain as a soluble peptide (Haass and
degeneration (Arendt et al., 1985; Arendt and Bigl, 1986).
Selkoe, 1993; Shoji et al., 1992), which raised the possibi-
Cell culture experiments have shown that the insoluble
lity that b-amyloid may also play a physiological role. This
b-amyloid fibrils have a neurotoxic effect (Pike et al., 1991;
is supported by cell culture studies providing evidence of a
Lorenzo and Yankner, 1994).
modulatory role of soluble b-amyloid on cholinergic neu-
The toxicity of b-amyloid plaques has been suggested to
rotransmission (see e.g., Auld et al., 2002). For example,
be affected by advanced glycation endproducts (AGEs),
solubilized b-amyloid at pM to nM concentrations strongly
formed by reaction of proteins with reactive sugars or
inhibits the potassium-stimulated release of acetylcholine
dicarbonyl compounds (M€ unch et al., 1994). AGEs detect-
from hippocampal slices (Kar et al., 2004) and decreases
ed in neuritic but not diffuse b-amyloid plaques in aged
activity of choline acetyltransferase but not AChE activity
Alzheimer patients (L€ uth et al., 2005), are able to cross-
in cholinergic SN56 cells (Pedersen et al., 1996). b-amy-
link proteins and to activate glial cells, thus contributing
loid peptides also decrease the intracellular acetylcholine
to plaque stability and plaque-induced inflammation in
concentration (Hoshi et al., 1997) and impair M1-mAChR
Alzheimer’s disease (M€ unch et al., 1997a, b, 1998, 2003).
associated signaling (Kelly et al., 1996) in primary septal
However, transgenic mice that express the Swedish dou-
or cortical cultures. Exposure of PC12 cells to b-amyloid
ble mutation of human APP (APPsw) show a surprisingly
resulted into significant decrase in nAChR which led to the
minimal correlation among the accumulation of insolu-
suggestion that b-amyloid can degenerate nAChR (Guan
ble Ab-peptides, neuronal losses and memory impairments
et al., 2001; Liu et al., 2001) which could explain the loss
(Irizarry et al., 1997; Westerman et al., 2002, for review,
of nAChR binding observed in Alzheimer brains (Nordberg,
see also Schliebs, 2005b). Additionally, there are reports of
1992; Teaktong et al., 2004). Otherwise, there a reports that
cognitively normal individuals with high b-amyloid burden
b-amyloid may affect nAChR by direct binding with high-
in their brains (Delaere et al., 1990). Thus, these novel
affinity to nAChR, in particular to the a7 subtype (Wang
aspects of b-amyloid actions have led to a re-evaluation
et al., 2000a, b), while other studies have been unable con-
of the amyloid hypothesis of Alzheimer’s disease (Hardy
firm these findings (Liu et al., 2001; Guan et al., 2003).
and Selkoe, 2002).
b-amyloid has been observed to act as an agonist of
An alternative hypothesis involves the roles of soluble,
a7 nAChR (Fodero et al., 2004) mediating the activation
low-molecular weight monomers, oligomers and protofi-
of the ERK2 MAP kinase signaling cascade (Dineley et al.,
brils of b-amyloid and their effects on neurons. It has been
2001, 2002), while other groups have reported inhibitory
shown that b-amyloid oligomers are synaptic-specific li-
actions of b-amyloid on a7 nAChR (Dineley et al., 2002;
gands, which are able to inhibit hippocampal long-term
Pettit et al., 2001; Tozaki et al., 2002; Grassi et al., 2003;
potentiation in brain slices and rat brains in vivo (Walsh
Lee and Wang, 2003), which appears to depend on the
et al., 2002b; Wang et al., 2002). Protofibrils induce elec-
concentration of b-amyloid, low concentration can activate,
trophysiological changes and neurotoxicity in cortical neu-
higher concentrations desensitize a7 nAChR (Dineley et al.,
rons (Hartley et al., 1999). In Alzheimer brains, it has been
2002). Therefore, parts of the cholinergic deficits produced
observed that the severity of neurodegeneration correlates
in Alzheimer’s disease as well as in transgenic APP mice
best with the pool of soluble b-amyloid than with the num-
could be attributed to the suppression of cholinergic func-
ber of insoluble b-amyloid plaques (McLean et al., 1999).
tions by b-amyloid peptides apart of cell death (Blusztajn
In different cell and animal models prefibrillar assemblies
and Berse, 2000). This is supported by findings in Alzheimer
of b-amyloid have been shown to induce neurotoxicity, elec-
patients, that the cholinergic deficits coincide with the de-
trophysiological changes and disruption of cognitive func-
position of b-amyloid plaques at the earliest histopatholog-
tion (Hartley et al., 1999; Walsh et al., 1999, 2002; Kayed
ical stages, before the onset of clinical symptoms (Beach
et al., 2003; Wang et al., 2002; Cleary et al., 2005), which
et al., 2000).
may explain why early onset cholinergic dysfunction is in
Recently, it has been shown that memory deficits in
progress before there is considerable plaque formation in
middle-aged transgenic Tg2576 mice that do not exhibit
Alzheimer’s disease. This is further supported by a recent
significant b-amyloid plaque load, are caused by the extra-
cell culture study demonstrating that only soluble oligomeric
cellular accumulation of a 56-kDa soluble b-amyloid as-
but not fibrillar b-amyloid (1–42) forms induced toxicity in
sembly (Ab 56), as Ab 56 purified from the brains of
cholinergic SN56.B5.G4 cells (Heinitz et al., 2006).
1632
impaired Tg2576 mice disrupted memory when admin-
istered to young rats (Lesn
e et al., 2006). It has been
suggested that Ab 56 impairs memory independently of
plaques, and may contribute to cognitive deficits associated
with Alzheimer’s disease (Lesn
e et al., 2006). However, it
remains to be elucidated whether Ab 56 exerts its action
by affecting also the cholinergic transmitter system.
Cholinergic dysfunction and tau protein
Neurofibrillary tangles, one of the hallmarks of Alzheimer’s
disease, represent intracellular inclusions formed by aggre-
gates of hyperphosphorylated microtubule-associated tau
protein and which are found in select neuronal populations
in Alzheimer’s disease (Kosik et al., 1986; Lee et al., 1991).
While in the brains of Alzheimer patients no tau mutations
have been described, pathogenic mutations in the tau genes
cause frontotemporal dementia (see e.g. Goedert and Jakes,
2005) suggesting that post-transcriptional alterations in tau
gene expression may contribute to the cognitive deficits in
Alzheimer’s disease presumably also by interacting with
the cholinergic transmission. Several studies have demon-
strated that activation of nAChR results in a significant in-
crease in tau phosphorylation, whereas mAChR activation
may prevent tau phosphorylation (Hellstrom-Lindahl et al.,
2000; Wang et al., 2003; see also Rubio et al., 2006, for
review). Nicotine-induced increase in tau phosphoryla-
tion at specific sites that were also hypophosphorylated in
Alzheimer’s disease, and is presumably mediated mainly
through the alpha7 subtype of nAChR (Wang et al., 2003).
Triple transgenic Alzheimer-like mice that overexpress mu-
tated human amyloid precursor protein, presenilin-1 and
tau (Oddo et al., 2003) developed age-and regional depend-
ent accumulation of plaques and tangles and progressive
deficits in cognition (Billings et al., 2005; Kitazawa et al.,
2005). Chronic nicotine administration to one-month-old
triple transgenic Alzheimer-like mice for five months did
not change soluble b-amyloid levels but resulted in a strik-
ing increase in phosphorylation and aggregation state of
tau, a finding that is presumably mediated through the loss
of alpha7 nAChR observed in 6-months-old triple trans-
genic mice (Oddo et al., 2005).
Cholinergic basal forebrain neurons have been shown to
demonstrate tau pathology both in patients with mild cog-
nitive impairment and in Alzheimer patients (Mufson et al.,
2002; Mesulam, 2004; Counts and Mufson, 2005; Ginsberg
et al., 2006a). In the adult human brain, six tau isoforms are
expressed through alternative splicing of a single tau gene
on chromosome 17 (Goedert et al., 1989a, b). Three iso-
forms consist of three tandem microtubule binding repeats,
R. Schliebs, T. Arendt
while the other three forms contain four microtubule bind-
ing repeats. Single cell gene expression profiling revealed a
shift in the ratio of three-repeat tau to four-repear tau in
individual human cholinergic basal forebrain neurons with-
in the nucleus basalis and CA1 hippocampal neurons dur-
ing the progression of Alzheimer’s disease but not during
normal aging (Ginsberg et al., 2006a). While the functional
significance of this shift still remains to be elucidated,
changes in tau isoform expression in vulnerable popula-
tions of neurons may contribute to the cholinergic cell loss
and cognitive deficits in Alzheimer’s disease.
Particular vulnerability of basal forebrain
cholinergic neurons to pathogenic stimuli
It is interesting to note that cholinergic cells located in
the pontine reticular formation are relatively preserved in
Alzheimer’s disease indicating that brain cholinergic neu-
rons demonstrate differential sensitivity to pathogenic in-
sults. This is emphasized by cell culture and in vivo studies
demonstrating that basal forebrain cholinergic neurons are
more susceptible to toxic agents such as aluminium, nitric
oxide, ethanol as compared to those in striatum and brain
stem (Arendt et al., 1981; Fass et al., 2000; Julka et al.,
1995). RN46A neuroblastoma cells from raphe nucleus,
when differentiated to cholinergic phenotype with ciliary
neurothrophic factor appeared to be more susceptible to
b-amyloid than those differentiated to serotoninergic phe-
notype with brain derived neurothrophic factor (Olesen
et al., 1998) suggesting that cholinergic neurons are more
susceptible to toxic agents than other neuronal cell types,
which may explain why non-cholinergic transmitter sys-
tems such as glutamate or GABA appear less affected in
Alzheimer’s disease (Armstrong et al., 2003).
Cholinergic cells differ from other neuronal cell types by
utilizing acetyl-CoA not only for energy production but also
for acetylcholine synthesis. Thus the particular vulnerability
and differential susceptibility of cholinergic neurons to var-
ious toxic conditions has been suggested to be due to dif-
ferent ratios of their acetyl-CoA energy producing and
acetylcholine synthesizing capacities. Cholinergic cells ap-
pear to have a higher demand for energy production and
therefore should respond more sensitive to energy (glucose)
deprivation (Szutowicz et al., 2006). Indeed, neurotoxic
compounds such as aluminium (Platt et al., 2001), nitric
oxide and reactive oxygen species (Law et al., 2001) have
been shown to contribute to the loss of central cholinergic
neurons by affecting acetyl-CoA and energy metabolism
(Jankowska et al., 2000; Szutowicz, 2001). Moreover, acute
stress has also been found to induce expression of the AChE
Cholinergic transmission and Alzheimer’s disease
gene and to increase brain AChE activity (Kaufer et al.,
1998), while in cell cultures oxidative stress has been ob-
served to differentially affect transcriptions factors which
were activated by cholinergic stimulation (Li et al., 1996).
In Alzheimer’s disease brain glucose utilisation as well as
some key enzymes of glucose metabolism are reduced (Bigl
et al., 1996, 2000). As insulin, insulin-like growth factors
and their receptors, molecules which are known to regulate
glucose metabolism in brain, are also affected in Alzheimer’s
disease, it has been hypothesized that insulin-dependent
functions may be of pathogenetic relevance in sporadic
forms of the disease (Fr€ olich et al., 1998; Bernstein et al.,
1999; Hoyer, 2004). A relationship between glucose meta-
bolism and cholinergic transmission and b-amyloid has also
been derived from animal experimental approaches (Bigl
et al., 2003; L€ offler et al., 2001; Mehlhorn et al., 1998)
suggesting functional links between cortical cholinergic
activity and glucose metabolism in cholinoceptive target re-
gions (for review, see also Schliebs, 2005a).
There is evidence that cholinergic cells are also suscepti-
ble to inflammatory conditions, and anti-inflammatory drugs
have been observed to attenuate inflammation-mediated cy-
totoxicity (see Wenk et al., 2000). The transcription factor
NFkB is a downstream signal molecule that may be acti-
vated by stimulation of both type 1 interleukin (IL)-1 recep-
tor and muscarinic cholinergic receptor-mediated signaling
transduction pathway. Thus IL-1b may interfere with the
cholinergic signal transduction cascade by inhibiting tran-
scription factor activation, thus providing another mecha-
nism by which IL-1b may induce cholinergic dysfunction in
Alzheimer’s disease (Schliebs et al., 2006).
The e4-allele of the apolipoprotein E gene has been at-
tributed to constitute a major genetic risk factor to develop
late-onset Alzheimer’s disease (Corder et al., 1993, 1998;
Cruz-Sánchez et al., 2000) and is assumed to affect the cho-
linergic deficit. However, neither the apolipoprotein E knock-
out nor the apolipoprotein E4 transgenic mice displayed any
changes in cholinergic parameters as compared to non-trans-
genic mice, suggesting that apolipoprotein E4 is not dele-
terious per se for the cholinergic system in mouse brain
(Bronfman et al., 2000; Fagan et al., 1998). Moreover, apol-
ipoprotein E deficiency did not increase the sensitivity to
cholinergic and spatial navigation deficits produced by ex-
citotoxic lesions of the nucleus basalis (Puolivali et al., 2000).
Cholinergic dysfunction and nerve
growth factor (NGF)
NGF is specifically implicated in protection and mainte-
nance of cholinergic neurons in the basal forebrain. It
1633
improves neuronal survival, increases sprouting of cholin-
ergic neurons in vitro and in vivo (Dekker et al., 1991;
Hefti et al., 1985) and may rescue cholinergic cells from
lesion-induced atrophy (Williams et al., 1986; Wilcox et al.,
1995; Winkler et al., 2000). Administration of exogenous
NGF to aged animals was found to reverse the age-related
atrophic changes (Fischer et al., 1987) and to improve spa-
tial memory (Fischer et al., 1991). However, the aging-
related cholinergic atrophy and cell loss in normal brain
as well as in Alzheimer’s disease is not complemented by
reductions in the levels of NGF (Hellweg et al., 1998;
Katoh-Semba et al., 1998; Murase et al., 1993; Narisawa-
Saito et al., 1996) as could be expected, which hints to a
functional loss of aging cholinergic neurons to respond to
NGF. Indeed, in aged rats, forebrain cholinergic neurons
demonstrated striking reductions in the retrograde transport
of NGF, and cholinergic cells that were no longer capable
to transport NGF appeared severely shrunken (Cooper et al.,
1994; deLacalle et al., 1996). Thus basal forebrain cholin-
ergic neurons seem to be particularly sensitive to failures
in NGF signalling that may induce cellular atrophy and
changes in gene expression (Sofroniew et al., 2001). The
recent development of transgenic mice that express a neu-
tralizing anti-NGF recombinant antibody (Capsoni et al.,
2000) added further evidence that failure in NGF signaling
contributes to cholinergic neurodegeneration. These anti-
NGFmice in which the levels of antibodies are three orders
of magnitude higher in adult than in newborn mice, demon-
strated age-dependent Alzheimer-like neurodegenerative
pathology including formation of amyloid plaques, hyper-
phosphorylated tau, and neurofibrillary tangles in cortex and
hippocamous (Capsoni et al., 2000). Aged anti-NGF mice
also displayed extensive neuronal loss throughout the cor-
tex, cholinergic deficits in the basal forebrain, and behav-
ioural deficits (Capsoni et al., 2000).
In addition to its protective function on basal forebrain
cholinergic cells, NGF signaling has also been shown to
influence expression and metabolism of APP (for review,
see e.g. Isacson et al., 2002). In primary cortical neuronal
cultures enhanced expression of APP and secretion of
sAPPa was observed following NGF treatment (Wang
et al., 2000c). Stimulation of PC12 cells with NGF caused
an increase in endogenous presenilin-1 level (Counts et al.,
2001), while trophic factor withdrawal-induced death of
PC12 cells, resulted into enhanced APP expression (Araki
and Wurtman, 1998). NGF stimulates APP promotor ac-
tivity in PC12 cells involving activation of Ras-MAP
kinase signaling, while NGF-induced secretion of sAPP
is mediated by a Ras-independent mechanism (Villa et al.,
2001).
1634
The chronic deprivation of NGF in the anti-NGF mice
(AD11) leads to basal forebrain cholinergic deficits and to
the formation and deposition of b-amyloid (Capsoni et al.,
2002), which provides in vivo evidence of a direct link
between NGF signaling and APP processing.
NGF was also observed to modulate the cholinergic con-
trol of APP prosessing. In PC12 cells transfected with the
M1-mAChR subtype, NGF promoted sAPPa secretion fol-
lowing M1 muscarinic agonist stimulation (Haring et al.,
1995). Similarly, treatment of mice with the selective M1
muscarinic agonist RS86 enhanced secretion of sAPPa, while
reducing the level of total APP and NGF in corticohippo-
campal regions (Seo et al., 2002). Chronic treatment of
transgenic Tg2576 Alzheimer mice with propentofylline, a
synthetic xanthine derivative known to stimulate synthesis
and release of NGF, resulted into increased NGF mRNA
level and a major shift in the balance of APP processing
from the amyloidogenic to the non-amyloidgenic pathway
compared to untreated controls (Chauhan and Siegel, 2003;
Chauhan et al., 2005), thus providing also in vivo evidence
of a modulatory function of NGF on APP metabolism.
In NGF-responsive cells, following stimulation of the
high-affinity NGF receptor, TrkA, we have observed in-
creased secretory non-amyloidogenic APP processing, while
a transcriptional regulation of APP expression is mediated
through the low-affinity neurotrophin receptor p75NTR
(Roßner et al., 1998b). This compares well with findings
in Alzheimer patients, a significant reduction in the expres-
sion of TrkA has been observed, while TrkB, TrkC and
p75NTR mRNA levels remained unchanged (for review, see
Salehi et al., 2004). Thus a loss of TrkA-mediated signaling
in Alzheimer’s disease may also affect APP processing.
Alternatively, the production of b-amyloid may influence
the membrane integrity of TrkA-bearing neurons resulting
into disruption of NGF signaling with severe consequences
on maintenaince of basal forebrain cholinergic cells (Salehi
et al., 2004).
b-amyloid may damage neurons either directly by inter-
acting with membrane components that initiate cell death
signaling or indirectly by activating astro-or microglia which
secrete pro-inflammatory cytokines. In a number of neuro-
blastoma cell lines including PC12, SK-N-BE, NIH3T3, and
SK-N-MC cells, it has been shown that p75NTR increases the
susceptibility of these cells to b-amyloid toxicity (Rabizadeh
et al., 1994; Yaar et al., 2002; Kuner et al., 1998; Perini et al.,
2002). p75NTR is reqired to induce the b-amyloid-mediated
cytotoxicity by interacting with b-amyloid (Yaar et al.,
2002) and initiating the p75NTR -mediated activation of cas-
pases-8 and 3 (Perini et al., 2002). Moreover, IL-1b and
TNFa produced by b-amyloid-activated microglia were
R. Schliebs, T. Arendt
found to potentiate the neurotoxic action of b-amyloid me-
diated through p75NTR (Perini et al., 2002).
In contrast to the findings in neuroblastoma cell lines, in
human primary neurons p75NTR was found to protect
against extracellular b-amyloid toxicity in a phosphatidy-
linositide 3-kinase-dependent but Akt-independent manner
(Zhang et al., 2003). This neuroprotective role of p75NTR
observed in human primary neuronal cell cultures is sup-
ported by in vivo studies. p75NTR immunoreactivity is de-
creased in basal forebrain cholinergic neurons of Alzheimer
patients (Salehi et al., 2000; Mufson et al., 2002) suggest-
ing that a lack of p75NTR predisposes to neuronal degen-
eration in Alzheimer’s disease (Mufson et al., 2002). This
compares well with observations in APPSwe=PS1 trans-
genic mice with high b-amyloid plaque load, revealing
increased p75NTR protein level in the absence of any neu-
ronal cell loss (Jaffar et al., 2001).
However, recent observations that the transition from
mild cognitive impairment to Alzheimer’s disease is char-
acterized by a selective reduction of cortical TrkA protein
but stable expression of cortical p75NTR (Counts et al.,
2004), indicates that mainly the NGF receptor imbalance
produces the deleterious effects on cholinergic basal fore-
brain function. However, chronic degeneration of cholin-
ergic basal forebrain neurons may also trigger reactive
mechanisms of repair involving the action of different tro-
phic factors such as brain-derived neurotrophic factor and
neurotrophin-3 (Durany et al., 2000).
Although the beneficial effects of NGF on neuronal
maintenance and rescue from damage appeared promising
to prove for the therapeutic potentials of NGF (Martinez-
Serrano and Bj€orklund, 1998; Rahimi and Juliano, 2001;
Roßner et al., 1996), the intracerebroventricular administra-
tion of NGF to Alzheimer patients (Eriksdotter-J€ onhagen
et al., 1998) and to rodents (Winkler et al., 2000) produced
a number of unwanted side effects. This may partly be due
to the diversity of cells that respond to NGF signaling
(Sofroniew et al., 2001). However, a recent study provided
evidence that NGF, when infused intraparenchymally to
rats with complete unilateral fornix transections, rescued
basal forebrain cholinergic neurons, but did not induce any
adverse effects at least over a two-week infusion period
(Tuszynski, 2000).
Enhancing cholinergic transmission as symptomatic
and palliative therapy of Alzheimer’s disease
Based on the assumption that the progressive decline of
cognitive function in Alzheimer’s disease mainly results
from decreased cholinergic neurotransmission, pharmaco-
Cholinergic transmission and Alzheimer’s disease
logical approaches to enhance basal forebrain cholinergic
pathways have been developed for symptomatic and pallia-
tive therapy (Mount and Downtown, 2006). A number of
acetylcholinesterase inhibitors including tacrine, donepezil,
rivastigmine and galantamine have been proved to enhance
cholinergic synaptic efficacy by preventing the breakdown
of acetylcholine and thus elevating and=or maintaining its
level in the synaptic cleft and to prolong its action on
postsynaptic muscarinic and nicotinic receptors (for review,
see, e.g. Giacobini, 2004; Lane et al., 2004; Birks, 2006;
Mount and Downtown, 2006; Nordberg, 2006). However,
acetylcholinesterase inhibitors produce only modest im-
provements in cognitive function (Bryson and Benfield,
1997; Frisoni, 2001; Gauthier, 2002; Giacobini, 2001;
Greenberg et al., 2000; Mohs et al., 2001; Winblad et al.,
2001) together with some unwanted side effects (Wilkinson,
1999; Dunn et al., 2000; Imbimbo, 2001), and a certain
portion of Alzheimer-patients does not even respond to this
treatment (Birks, 2006; Mount and Downtown, 2006).
Therefore, it has to taken into consideration that the chron-
ic treatment with AChE inhibitors may also induce com-
pensatory mechanisms at the cholinergic synapse that are
counteracting to the desired action of the drugs. AChE
inhibitor-mediated chronically increased level of acetylcho-
line at the synaptic cleft should lead to an overactivation of
postsynaptic receptors followed by up-regulations of var-
ious postsynaptic events including inmediate early gene
(IEG)-induced enhanced expression of AChE. Thus, the
endogenously induced production of AChE may be respon-
sible for the loss of efficacy of systemically applied AChE
inhibitors with the time of treatment (Hoyer and Riederer,
2003; Riederer and Hoyer, 2005).
Recent progress in understanding the role of BuChE in
dementia (Ballard et al., 2005; Greig et al., 2005; Lane
et al., 2006; Tasker et al., 2005), as well as the availability
of selective inhibitors of BuChE (Kamal et al., 2006; Greig
et al., 2005) has raised the question whether selective tar-
geting of either AChE or BuChE in dementing disorders
may have greater clinical efficacy (Tasker et al., 2005),
which however must await further clinical trials.
An alternative approach to enhance cholinergic neuro-
transmission includes the increase of acetylcholine release
by activation of presynaptic nicotinic cholinergic receptors
through appropriate nicotinic agonists (Oddo and LaFerla,
2006). Recently, the subtype-selective nicotinic acetylcho-
line receptor ligand SIB-1553A has been shown to improve
cognitive deficits in Alzheimer patients in a similar mag-
nitude as the acetylcholinesterase inhibitor donezepil
(Bontempi et al., 2003), suggesting that nicotinic receptor
activation may represent another promising strategy to treat
1635
cognitive deficits in Alzheimer’s disease. This is further
emphasized by findings that chronic administration of nico-
tine to transgenic mice carrying the Swedish mutation of
human APP, considerably reduced brain beta-amyloid pla-
que deposition (Nordberg et al., 2002). Recently, long-term
tobacco smoking has been observed to attenuate b-amyloid
deposition in the entorhinal cortex of normal elderly indi-
viduals (Court et al., 2005) which further underlines the
potential of developing a ‘‘nicotinic’’ treatment strategy.
Besides the administration of NGF, transplantation of ace-
tylcholine-producing cells may also provide a useful tool to
restore injured cholinergic neurotransmission. The substan-
tial and persistent memory losses produced by chronic etha-
nol intake were associated with an impairment of cholinergic
function, and wcould be reversed by cholinergic-rich trans-
plants into cortex and hippocampus (Arendt et al., 1988).
Hippocampal grafts of fibroblasts engineered to produce
acetylcholine have been found to be sufficient to improve
behavioral performance following unilateral fimbria-fornix
lesion (Dickinson-Anson et al., 1998). Although fimbria-
fornix lesion disrupts a number of hippocampal transmitter
systems, the lesion-induced deficits in water maze perfor-
mance could be attenuated by a target-specific replacement
of acetylcholine in the hippocampus. Immortalized brain
endothelial cells genetically modified to express ChAT
and=or the vesicular acetylcholine transporter have also been
suggested as a promising tool for improving altered choli-
nergic function in the central nervous system (Malo et al.,
1999). More recently, the potential of neural stem cells to
acquire cholinergic characteristics has been tested. A neural
stem cell line was transplanted into the septum=diagonal
band nuclei of young and adult rodents previously sub-
jected to a lesion of the fimbria-fornix pathway (Doering
and Snyder, 2000). Subpopulations of the grafted cells
acquired a cholinergic neuronal phenotype and expressed
ChAT and p75NTR, indicating the potential of this stem cell
line to rescue damages within the basal forebrain cholinergic
system. Similarly, it has been demonstrated that condition-
ally immortal neuroepithelial stem cells (MHP36), grafted
into the cortex or basal forebrain of rats with basal forebrain
cholinergic lesions produced a restoration of spatial learning
in the water maze already detectable six weeks after the
transplantation (Grigoryan et al., 2000), further suggesting
that the development of immortal human stem cell lines may
provide a strategy to treat neurodegenerative disorders.
Conclusions
Basal forebrain cholinergic dysfunctions in Alzheimer’s
disease appear to play an important role in the pathogenesis
1636
of Alzheimer’s disease. The correlation of clinical demen-
tia ratings with the decrease in a number of cholinergic
markers suggested an association of cholinergic hypofunc-
tion with cognitive deficits, which has been confirmed by a
number of experimental studies both in animals and hu-
mans. Abnormal changes in the regulation of cholinergic
transmission very early in life has been assumed to con-
tribute to the later development of mild cognitive impair-
ments, further supporting the suggestion of a key role of
the cholinergic system in functional processes that lead to
Alzheimer’s disease. While there is strong evidence that
cortical cholinergic transmission plays a major role in the
controling APP processing and b-amyloid plaque for-
mation as well as phosphorylation of tau protein, there is
still a debate whether the cholinergic deficits observed in
Alzheimer’s disease are a primary event or secondary to the
pathomorphological features of the disease.
Acknowledgement
This study was supported by the Interdisciplinary Centre for Clinical
Research (IZKF) at the Medical Faculty of the University of Leipzig.
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