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PERSPECTIVES IN PHARMACOLOGY
Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy (Augusta Campus) (A.V.T.), Small Animal Behavior Core (A.V.T.), and Alzheimer's Research Center and Department of Pharmacology and Toxicology (A.V.T., J.J.B.), Medical College of Georgia, Augusta, Georgia; and Department of Veterans Affairs Medical Center, Augusta, Georgia (A.V.T., J.J.B.)
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Abstract |
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The Cholinergic Hypothesis |
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). For more
than 20 years, studies of the brains of those with advanced age and
Alzheimer's disease (AD) have consistently found damage or abnormalities in
these pathways (particularly basal forebrain projections) that appeared to
correlate well with the level of cognitive decline. As a result, the so-called
"cholinergic hypothesis" was developed, which essentially states
that a loss of cholinergic function in the central nervous system contributes
significantly to the cognitive decline associated with advanced age and AD
(reviewed, Bartus, 2000).
Extensive literature from animal experiments supports the human data described
above. In fact, the importance of cholinergic function in the brain to
learning and memory was first recognized more than 30 years ago after
cholinergic antagonists (specifically antimuscarinic agents) were found to
impair memory in rats (Deutsch,
1971). Considerable additional evidence now supports this early
work, and antimuscarinic agents such as scopolamine and atropine have been
shown to impair memory performance in a variety of behavioral paradigms in
rodents. Such tests include passive (inhibitory) avoidance procedures, operant
(matching and nonmatching) tasks, and spatial learning (and working memory)
procedures such as water maze and radial arm maze tasks (reviewed,
Decker and McGaugh, 1991).
These data have been further extended to include selective muscarinic (i.e.,
M1) antagonists such as pirenzepine
(Hunter and Roberts, 1988) as
well as centrally acting nicotinic-cholinergic antagonists such as
mecamylamine (Levin, 1992).
Both muscarinic antagonists (Terry et al.,
1993a; Vitiello et al.,
1997) and nicotinic antagonists
(Elrod and Buccafusco, 1991;
Newhouse et al., 1994) have
also been shown to impair memory performance in monkeys and humans.
Furthermore, lesions in animals that damage cholinergic input to the neocortex
or hippocampus from the basal forebrain (e.g., nucleus basalis magnocellularis
and medial septum/diagonal band) disrupt performance of the same memory tasks
that are impaired with cholinergic blockade (reviewed in
Decker and McGaugh, 1991). It
should be noted that damage to similar basal forebrain regions in humans (as a
result of arterial aneurysms, or resection of an arteriovenous malformation)
has also been associated with severe memory deficits
(Damasio et al., 1985).
As a result of the findings cited above (i.e., in both humans and animals),
the primary therapeutic approach to date to address the cognitive loss
associated with AD has been that of a cholinergic replacement strategy. This
approach has been attempted using muscarinic and nicotinic-cholinergic ligands
and acetylcholinesterase inhibitors (reviewed in
Buccafusco and Terry, 2000). To
date, however, only the data derived from clinical trials with
acetylcholinesterase inhibitors (e.g., tacrine, donepezil, rivastigmine, and
galantamine) have provided convincing evidence of an adequate level of
efficacy and reliability in AD balanced with an acceptable burden of side
effects. Accordingly, these agents are the only drugs currently approved by
the United States for clinical use in AD. Due to the modest risk of
hepatotoxicity associated with tacrine, the latter three compounds listed
above are generally preferred. Agents such as the glutamate antagonist
memantine have recently been associated with improvements in advanced AD
symptomatology and may suggest one new approach to therapy.
|
Challenges to the Cholinergic Hypothesis |
|---|
)
reported that the activity of acetylcholinesterase (AChE) and choline
acetyltransferase (ChAT) was not reduced in post mortem neocortical tissues of
those recently diagnosed with mild AD. As a result, the authors suggested
that: 1) it is unlikely that a cholinergic marker could be used as an early
indicator of AD; 2) it is unlikely that a cholinergic deficit could be
identified prior to the patient becoming symptomatic; and 3) only the patients
with more severe disease should be a target for cholinergic treatment. In
addition, DeKosky and colleagues (DeKosky
et al., 2002) failed to detect any reduction in ChAT activity in a
number of cortical regions studied in patients diagnosed with MCI or mild AD,
and in fact, activity was actually up-regulated in the frontal cortex and
hippocampus of those with MCI. In another study, neurons containing ChAT and
the vesicular acetylcholine transporter protein were preserved in the nucleus
basalis in individuals with MCI and early AD
(Gilmor et al., 1999).
Collectively, the articles cited here have led to editorials (e.g.,
Morris, 2002) that have
further challenged the assumptions and validity of the cholinergic hypothesis
as it applies to AD (particularly in the early stages).
It should be noted that while the aforementioned studies and subsequent
editorials provide valuable data and discussion, some of the conclusions
appear somewhat premature. Since neither ChAT nor AChE are rate-limiting
cholinergic enzymes, they are unlikely to accurately reflect cholinergic
function in the living patient, and a host of factors that were not assessed
(or even mentioned in these studies) could be compromised in cholinergic
neurons before changes in these enzymes would be observed. Examples from the
post mortem AD literature include alterations in high-affinity choline
up-take, impaired acetylcholine release, deficits in the expression of
nicotinic and muscarinic receptors, and dysfunctional neurotrophin support
(reviewed in Auld et al.,
2002). Each of these important factors deserves further
discussion. Alterations in high-affinity choline transport (i.e., the
rate-limiting process for acetylcholine synthesis) have been observed in post
mortem AD brains (Slotkin et al.,
1990) as well as in the brains of transgenic mice that exhibit
AD-like amyloid pathology (Apelt et al.,
2002). An increase in choline flux across the membranes of
neuronal cells exposed to 
-amyloid has also been hypothesized to
contribute to the selective vulnerability of cholinergic neurons in AD
(Allen et al., 1997). The
results of experiments by Kar and colleagues
(Kar et al., 1998) using rat
hippocampal slices indicated that under acute conditions, amyloid peptides
could inhibit the uptake of choline and decrease endogenous acetylcholine
release without exhibiting effects on ChAT activity. Interestingly, in earlier
studies, Nilsson and colleagues (Nilsson
et al., 1986) detected a deficit in potassium evoked acetylcholine
release in post mortem cortical tissue from AD patients. A variety of studies
have reported reductions in central nicotinic receptors in aged subjects and
those who suffered from AD or other age-related disease in which dementia was
present (e.g., Lewy Body disease and Parkinson's disease; see
Perry et al., 2000). In AD,
high-affinity 
4 containing nicotinic receptors appear to be more
significantly reduced than either 3 or 7 containing receptors,
although decreases in 7 binding sites have been observed in Lewy Body
disease (see review, Picciotto and Zoli,
2002). This finding suggests that nicotinic receptor subtypes may
be differentially reduced in different forms of dementia.
There is a considerable amount of evidence to suggest that nerve growth
factor (NGF) support to cholinergic neurons in the basal forebrain of AD
patients is deficient leading to atrophy and possibly cell death. While there
does not appear to be a deficiency in the synthesis or availability of NGF
protein in the hippocampus or neocortex in AD brains, substantial evidence
suggests that retrograde transport of the neurotrophin and signal transduction
via the high-affinity tyrosine receptor kinase (TrkA receptor) is compromised
(see Mufson, 1999). While not
demonstrated specifically in the cholinergic phenotype, deficits in axonal
transport in cortical neurons have also been reported to occur in AD
(Dai et al., 2002). This
finding highlights a fundamental cellular process that may be disrupted in
many neuronal populations in AD brains including cholinergic neurons, and
further, deficits in axonal transport could underlie the deficits of
retrograde transport of NGF. It is certainly conceivable that early subtle
deficits in both retrograde and anterograde axonal transport could precede
measurable deficits in many cholinergic markers including ChAT or AChE. For a
graphic summary of the information provided in this section, please refer to
Fig. 1.
|
An additional issue that is important to address in regard to the recent
challenges to the cholinergic hypothesis (as well as many of the reports that
support the hypothesis) relates to the condition of the tissue samples
studied. It should not be understated that the collection of post mortem human
tissues for neurochemical analysis involves unavoidable delays that can
compromise the viability of the tissues analyzed. While the studies cited
above report impressive post mortem intervals ranging from approximately 4 to
12 h, this contrasts with animal studies in which post mortem intervals often
involve a matter of minutes. Therefore, unavoidable tissue deterioration and
variability in the data associated with post mortem AD brains pose a
significant challenge, an issue that underscores the importance of the
development and use of appropriate animal models of AD. As better in vivo
imaging methods become more widely available, ambiguities related to
cholinergic function in the central nervous system of living patients
suffering from MCI or early AD will likely become better elucidated.
Interestingly, several in vivo imaging studies conducted to date in AD
patients appear to support the cholinergic hypothesis. For example, PET
studies using [11C]N-methylpiperidin-4-yl-propionate
indicate that cortical acetylcholinesterase activity is indeed reduced in AD
patients (Kuhl et al., 1999).
[11C]Nicotine-based PET studies indicate that nicotinic receptor
deficits are in fact an early phenomenon in AD, and these reports further
suggest that cortical nicotinic receptor deficits significantly correlate with
the level of cognitive impairment
(Nordberg, 2001). Other PET
studies employing the nonselective muscarinic ligands
[123I]quinuclidinyl benzilate and
[11C]N-methyl-4-piperidyl benzilate indicate both age- and
AD-related decreases in binding in neocortical regions (see
Zubieta et al., 2001).
Moreover, single photon emission computerized tomography (SPECT) studies using
[123I]benzovesamacol binding indicate that the vesicular
acetylcholine transporter is reduced throughout the entire cerebral cortex and
hippocampus in early onset AD patients
(Kuhl et al., 1996).
|
Aging and Brain Cholinergic Neurons |
|---|
) examined whole brain
synthesis of acetylcholine in aged mice from 3 to 30 months of age. They
reported that the biosynthesis of acetylcholine (measured by injection of a
radio-labeled precursor) declined by up to 75% in the 30 month-old animals.
Mild hypoxia further decreased acetylcholine synthesis by 90%. Moreover, aged
cholinergic neurons were more impaired in their ability to release
acetylcholine following potassium stimulation than they were in their ability
to synthesize the transmitter (Gibson and
Peterson, 1981). Subsequent in vivo microdialysis methods largely
confirmed these early findings (e.g., Wu
et al., 1988). The concept that aged brain cholinergic neurons
function relatively normally until stressed has been supported through
experiments that used various methods to increase acetylcholine output
(Meyer et al., 1986;
Gilad et al., 1987;
Moore et al., 1996) or that
damage cholinergic neurons (Burk et al.,
2002). It seems reasonable to conclude, therefore, that any
sustained insult to forebrain cholinergic neurons could interfere with the
ability of these cells to provide sufficient transmitter release for normal
function. Sarter and his coworkers (Burk et
al., 2002) tested this possibility directly in a longitudinal
series of experiments in which chemical lesions of basal forebrain cholinergic
neurons were created in young rats with the aim of producing only limited loss
of basal forebrain cholinergic cells. The rats had been previously well
trained in the performance of a sustained attention task. Whereas initially
there was a similar degree of task performance in both experimental groups, a
significant dissociation between lesioned and control rats (in terms of task
efficiency) did not occur until the animals reached 31 months of age, when the
lesioned group exhibited significant task impairment. The results of these
studies in aged rodents become more relevant to the topic of this article
considering the observation that most of the age-related changes pertained
specifically to dynamic aspects of brain cholinergic neurons. In many of the
studies cited above and in many other reports, indirect measures of standard
cholinergic markers (as might be determined from autopsied tissues) often do
not show such dramatic age-related differences. |
Anticholinergic Drugs in Elderly Subjects and AD Patients |
|---|
;
Flicker et al., 1992) and in
subjects with AD when compared with nondemented elderly subjects
(Sunderland et al., 1987).
Some years ago we also investigated the issue of age-related sensitivity to
anticholinergics and compared the effects of scopolamine and the selective
peripherally acting muscarinic antagonist glycopyrrolate on a series of
cognitive paradigms administered to healthy elderly (55-67 years old) and
young (28-47 years old) volunteer subjects
(Ray et al., 1992). For each
test administered, the results were compared directly to those produced by
glycopyrrolate. The scopolamine data are reorganized and reproduced in
Fig. 2, A and B. Glycopyrrolate
did not significantly affect baseline test scores (data not shown). We also
measured drug levels in the subjects and found them to be similar between the
two groups. As indicated in Fig.
2A, the elderly subjects were impaired relative to their younger
cohort in their performance of the selective reminding task, both for the
consistent long-term retrieval and the delayed versions. In particular,
elderly subjects exhibited a rapid decline in task performance with dose in
the delayed version of the task that involved the learning and recall of new
words in the selective reminding task. Elderly subjects also were impaired by
the highest dose of scopolamine on their performance of the paired associates
learning task. Younger subjects were not affected by this less cognitively
demanding task (associated word pairs are formed during rehearsal).
Performance of the symbol digit modality task was also impaired in the elderly
subjects after receiving the highest dose of scopolamine
(Fig. 2B). This task requires
the subject to use a key to substitute numbers for meaningless geometric
designs and requires the efficiency of multiple mechanisms in both
hemispheres. As with the symbol digit modality task, the digit span task was
performed less efficiently by the elderly cohort at baseline, but unlike the
symbol digit modality task, there was no further decrement with scopolamine.
Digit span is a crude measure of attention or immediate memory. The inability
of scopolamine to further impact this aspect of cognition was confirmed by the
lack of effect of the drug in the continuous performance task, which requires
sustained vigilance. In the more difficult CPT-AX version (see
Fig. 2B) of the continuous
performance task, the elderly appeared to be more affected by scopolamine, but
relative to the effects of glycopyrrolate, there were no significant
differences between the two groups. Overall, results of this study are
consistent with the general impairment of elderly subjects at baseline on
certain cognitive tasks. They are also consistent with the marked sensitivity
to muscarinic receptor blockade exhibited by the elderly. Surprisingly, tasks
of attention and sustained vigilance were affected to a much lower degree than
were tasks of immediate recall and delayed recall.
|
|
Amyloid and the Cholinergic System |
|---|
). Therefore, theories concerning the proximal cause
of AD should account for this selective vulnerability of neurons comprising
basal forebrain cholinergic pathways. Since the overexpression and deposition
of brain amyloid probably plays some role in the neurodegeneration associated
with AD, the relationship between amyloid deposition and cholinergic neuron
activity is certainly of interest. Interestingly, agonists partially selective
for the M1 subtype of the muscarinic-cholinergic receptor have been reported
to elevate the nonamyloidogenic amyloid precursor protein (-APPs) and
decrease amyloid- (A) levels
(Muller et al., 1997;
Fisher et al., 2002). This
effect on APP processing appears to occur via the ability of these drugs to
use downstream signaling pathways that involve the activation of protein
kinase C and mitogen-activated protein kinase
(Haring et al., 1998). M1
agonists also may decrease 
protein phosphorylation in vitro and in vivo
(Sadot et al., 1996;
Genis et al., 1999), another
potential disease-modifying effect of this class of compounds, as
hyperphosphorylated protein is linked to cellular disruption by
neurofibrillary tangles.
The activation of nicotinic acetylcholine receptors also may produce
disease-modifying actions in AD. For example, the ability of nicotine to evoke
neuroprotective effects has been demonstrated in both in vitro and in vivo
models of neural toxicity (Owman et al.,
1989; Kihara et al.,
1997). The mechanism for nicotine's neuroprotective actions may
involve the drug's ability to transiently increase intracellular calcium with
downstream actions to increase the synthesis of various neurotropic factors
and their receptors (e.g., Dajas-Bailador
et al., 2000; Jonnala et al.,
2002). In fact, nicotine has been shown to inhibit the development
of cellular toxicity induced by A peptides (see
Woodruff-Pak et al., 2002).
Clearly, the degeneration of basal forebrain cholinergic neurons, which depend
for their viability on continuous neurotrophic influence, could lead to both a
cycle of decreasing stimuli for factors associated with cell survival and for
emphasis of the production of neurotoxic forms of A peptides. These
characteristics of basal forebrain cholinergic neurons fail to provide an
explanation as to their selective vulnerability to the disease process.
Nevertheless, it has been shown that 7 nicotinic acetylcholine
receptors can serve as high-affinity binding sites for A peptides
(Wang et al., 2000). Moreover,
A peptides can block the functional interaction of nicotinic agonists
with their receptors on hippocampal neurons
(Liu et al., 2001). The
potential blockade of basal forebrain and hippocampal nicotinic receptors by
endogenous A peptides has implications not only for the cognitive
decline associated with early stages of the disease process but also suggests
a mechanism for the targeting of the AD-related toxic peptides to neural cells
expressing 7 nicotinic receptors.
Thus, failure of the dynamics of cholinergic neurotransmission that is
associated with aging and with early stages of AD could contribute to a cycle
of neurotoxicity in advance of any detectable change in standard cholinergic
marker enzymes or even before the deposition of amyloid plaques
(Selkoe, 2002;
Woodruff-Pak et al., 2002).
This possibility is suggested by the finding that in certain transgenic
strains of mice that overexpress mutated human APP, cognitive decline occurs
in advance of the deposition of significant amounts of amyloid material
(Holcomb et al., 1999;
Kotilinek et al., 2002).
|
Cholinergic-Based Therapeutic Strategies (Present and Future Considerations) |
|---|
). These
so called "noncognitive" symptoms of AD increase caregiver burden,
significantly raise the direct costs of care, and result in earlier
institutionalization (reviewed Eustace et
al., 2002). A number of studies now indicate that the standard
therapy for cognitive dysfunction in AD (i.e., the acetylcholinesterase
inhibitors) are associated with improvement in a number of behavioral symptoms
including depression, psychosis, agitation, and a delay in nursing home
placement (reviewed, Cummings,
2003). Such findings provide an additional rationale for the use
of cholinergic-based therapies in AD.
Cholinergic abnormalities (which correlate with the degree of memory
decline) have also been observed in association with neurodegenerative
conditions other than AD such as Parkinson's disease, dementia with Lewy
bodies (reviewed, Perry et al.,
1999), and most recently, vascular dementia (reviewed,
Grantham and Geerts, 2002).
Accordingly, the use of acetylcholinesterase inhibitors has to a limited
extent been studied in these patient populations. To date, rivastigmine has
been observed to benefit patients suffering from dementia with Lewy Bodies and
Parkinson's disease, and galantamine has been found to benefit those suffering
from vascular dementia and AD with cerebrovascular disease (reviewed in
Cummings, 2003).
It should also be noted that cholinergic agents including cholinesterase
inhibitors (Terry et al.,
1993b; Furey et al.,
2000), muscarinic agonists
(Ruske and White, 1999), and
nicotinic agonists (Terry et al.,
2002) have been shown to enhance learning and memory and/or
attention in young unimpaired subjects. Hence, a cholinergic strategy to
memory enhancement may have a wider application than merely the conditions
(described above) in which cholinergic function is (significantly) impaired.
Schizophrenia and other disorders in which cognitive dysfunction and
distractibility are observed (e.g., attention deficit hyperactivity disorder)
offer just a couple of examples. Currently, several cholinergic-based
treatment strategies are in fact being pursued in the early phases of clinical
trials for treatment of the cognitive deficits associated with
schizophrenia.
|
Concluding Remarks |
|---|
) may represent an attempt by cholinergic neurons under stress
to compensate for functional impairments in transmitter release. Accordingly,
there remains a host of rational drug development approaches related to
central cholinergic neuronal function in memory disorders that may indeed pay
further dividends in the future. Such approaches involve the development of
novel and selective cholinesterase inhibitors (with more innocuous side effect
profiles) muscarinic and nicotinic-cholinergic ligands, and methods to enhance
growth factor (NGF) support to central cholinergic neurons. Such therapies may
not only afford cognitive improvements and the amelioration of adverse
behavioral symptoms in AD but also may provide neuroprotective and
neurotrophic actions that could be beneficial in several forms of dementia as
well as other debilitating conditions such as schizophrenia. |
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: AD, Alzheimer's disease; MCI, mild cognitive
impairment; AChE, acetylcholinesterase; ChAT, choline acetyl transferase; NGF,
nerve growth factor; PET, positron emission tomography; APP, amyloid precursor
protein; A, amyloid-.
Address correspondence to: Dr. Alvin V. Terry Jr., UGA College of Pharmacy, CJ-1020, The Medical College of Georgia, Augusta, GA 30912-2450. E-mail: aterry{at}mail.mcg.edu
|
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Abstract
The Cholinergic Hypothesis
