Posted 7 April 2000
Interviewed by Chris Wiehl
ARF: Outline for us what you think are the steps lead to AD pathogenesis?
What role do beta amyloid and tau play in AD? Are they related or independent
Mesulam: Amyloid plaques (AP) and neurofibrillary tangles (NFT)
are the two diagnostic markers of Alzheimer's disease (AD). The neuropsychological
features of AD are closely correlated with the distribution of the NFT and
therefore favor a disease process revolving around neurofibrillary degeneration.
The genetics, however, favor a disease process revolving around the AP,
principally because mutations in the amyloid precursor protein (APP) are
sufficient to cause AD. The inability to reconcile these two aspects of
AD has prevented the formulation of a unified theory of pathogenesis.
My hypothesis of AD pathogenesis shows that all genetic causes and risk
factors of AD (amyloid mutations, presenilin mutations, ApoE4, estrogen
deficiency, multiple trauma, aging) can increase the physiological burden
of neuroplasticity. It is hypothesized that the resultant intensification
of the plasticity burden leads to an initially adaptive upregulation of
tau phosphorylation and APP turnover, to the subsequent formation of NFT
and AP as independent consequences of excessive plasticity-related cellular
activity, and to the eventual loss of neurons, dendrites and synapses as
the ultimate expression of plasticity failure. The two pathological markers
of AD are therefore independent manifestations of a more fundamental process
through which the many different genotypes of AD cause an identical clinical
and neuropathological phenotype.
ARF: How do you account for the anatomical pattern and cellular
specificity in the progression of AD?
Marsel Mesulam: All AD-promoting factors are likely to perturb
processes that normally facilitate neuroplasticity. The hypothesis is based
on the assumption that the resultant barriers to neuroplasticity occur at
downstream dendritic and synaptic sites and that they trigger a reactive
(or compensatory) upstream intensification of plasticity-related perikaryal
activity. In other words, AD-promoting factors create a setting where neurons
must work harder to meet neuroplasticity needs at their axonal and dendritic
terminals. Over many years, such compensatory processes would lead to chronically
high and eventually unsustainable levels of plasticity-related cellular
ARF: Is there evidence for enhanced plasticity-related cellular
activity in experimental models or AD brains?
Marsel Mesulam: In vivo and in vitro experiments show that high
levels of neuroplasticity tend to be associated with the increased expression
and phosphorylation of tau (Brion et al., 1994; Black, 1996; Busciglio et al., 1987; Lovestone and Reynolds, 1997; Trojanowski et al., 1993; Viereck et al., 1989). For example, the olfactory bulb of the adult rat, a region that
continues to show very active neuroplasticity, expresses particularly high
levels of the more extensively phosphorylated, fetal forms of tau (Viereck et al., 1989; Lovestone and Reynolds, 1997). Furthermore, transfected PC12 cells overexpressing tau extend
neurites more rapidly, and neurite extension in response to NGF is associated
with a 10-20-fold induction of tau (Drubin et al., 1985; Esmaeli-Azad et al., 1994).
In the course of the processes that lead to AD, a chronically high demand
for plasticity-related activity could thus upregulate the expression of
tau, favor its phosphorylation, and potentially promote the polymerization
of tau into NFT. The NFT produced by such a sequence of events would initially
appear within limbic-paralimbic neurons because these neurons have the highest
baseline levels of plasticity and would thus have the highest exposure to
compensatory upregulations of plasticity-related cellular activity.
The resultant cytoskeletal dysfunction in these limbic-paralimbic neurons
would eventually lead to a degeneration of their dendrites and a loss of
their synapses at axonal projection targets. The adjacent limbic and paralimbic
neurons (many of which share the same connectivity patterns) would then
face at least two additional plasticity demands: 1) more reactive synaptogenesis
at their projection targets in order to replace the synapses originally
provided by the degenerated axons of adjacent NFT-containing neurons, and
2) more local dendritic remodeling to receive the synapses which can no
longer be accommodated by the degenerated dendrites of adjacent NFT-containing
neurons. Because of the downstream barriers to plasticity, these attempts
at reactive remodeling would be relatively ineffective and would also induce
an excessive upstream intensification of plasticity-related neuronal activity,
eventually leading to the formation of NFT in these additional neurons.
This sequence of events would promote the "horizontal" spread
of NFT within the tightly interconnected components of limbic-paralimbic
The loss of dendrites and synapses belonging to limbic-paralimbic neurons
would eventually increase the plasticity burden of the association cortices
with which they are reciprocally interconnected. These association areas
would need to accelerate dendritic remodeling to cope with the loss of inputs
from limbic-paralimbic neurons and would also need to remodel axonal endings
to cope with the loss of synaptic sites at their limbic targets. This would
cause a "vertical" expansion of the disease during which the neurofibrillary
degeneration (and eventually cellular death) would spread centrifugally
from limbic-paralimbic areas to association neocortex.
In support of this scenario, tangle-bearing hippocampal neurons show more
extensive dendritic trees than immediately adjacent tangle-free neurons,
suggesting that NFT formation may be accompanied or preceded by increased
plasticity (Gertz, 1990). Furthermore, tau mRNA is increased in the hippocampus,
but not in the visual cortex or cerebellum, of patients with AD (Barton et al., 1990). The initial stages of AD are also associated with increased tau
in the CSF (Galasko et al., 1997), suggesting that an upregulation of this protein occurs at a time
when the NFT are undergoing a steep increase in density and distribution.
Animal experiments show that injury- and denervation-induced neuroplasticity
can also lead to an upregulation of APP (Banati et al., 1993; Chauvet et al., 1997; Wallace et al., 1993; Beeson et al., 1994). Fimbria-fornix lesions in adult rats, for example, elicit a marked
accumulation of APP immunoreactivity in the denervated areas within the
hippocampus (Beeson et al., 1994). Such reactive APP accumulation may be quite selective. In the
case of the fimbria-fornix lesions, it seems to occur predominantly in the
CA1 region but not in the dentate gyrus. In the course of events leading
to AD, an initial upregulation of APP would be expected to occur at sites
of maximal plasticity burden, namely in limbic-paralimbic areas and their
axonal projection targets. This APP would then be processed into the sAPP
and Aß moieties, giving rise to complex combinations of neurotrophic
and neurotoxic effects. The released Aß would first have a soluble
form and would diffuse within the extracellular fluid in the form of 10-100
kDa monomers and oligomers (Kuo et al., 1996). Upon exceeding local concentration thresholds, this Aß
would be expected to form fibrils and condense into initially inert diffuse
plaques which would eventually mature into neurotoxic structures. The formation
of plaques by local condensation after the diffusion of the amyloid from
sites of upregulation, the fact that these sites can overlap with NFT-prone
limbic-paralimbic neurons or their widespread projection targets, the apparent
regional selectivity of plasticity-induced APP accumulation, and the initial
inertness of the deposited amyloid may explain why plaques do not mirror
the distribution of the NFT, and why they do not necessarily display a spatial
and temporal distribution that fits the clinical features of the dementia.
The premature development of NFT and Aß deposits in the brains of
ex-boxers provides further circumstantial support for the contention that
a heightened state of neuroplasticity (in this case, injury-induced) can
trigger the neuropathological changes of AD (Tokuda et al., 1991; Geddes et al., 1996). This is perhaps why head injury and stroke have both been implicated
as risk factors for AD (Salib and Hillier, 1997; Snowdon et al., 1997). However, such relationships are probably relevant only when the
injury is widespread, chronic, and when it occurs on a background of additional
factors which erect downstream barriers to neuroplasticity. Otherwise, all
neuronal diseases would eventually lead to AD pathology.
ARF: Can you describe the significance of cholinergic neuron pathology
in AD brains, specifically as it relates to your neuroplasticity model?
Marsel Mesulam: A severe depletion of cortical cholinergic innervation
is one of the most consistent features in the neuropathology of AD (Geula and Mesulam, 1996). The cholinergic innervation of the cerebral cortex arises from
the nucleus basalis of Meynert, a limbic structure that maintains an unusually
high level of plasticity into late adulthood (Arendt et al., 1995). Neurons of the nucleus basalis are consequently among the very
first cells of the brain to display an accumulation initially of hyperphosphorylated
tau and then of NFT (Mesulam, 1996). Numerous experiments have shown that cholinergic neurotransmission
plays an essential role in supporting reactive and experience-induced synaptic
reorganization in the cerebral cortex (Baskerville et al., 1997; Kilgard and Merzenich, 1998; Zhu and Waite, 1998). Furthermore, cortical cholinergic innervation also promotes the
alpha-secretase pathway and therefore the release of the neurotrophic sAPP
moieties (Nitsch et al., 1992). The early loss of cholinergic innervation in AD could thus contribute
to the acceleration of the pathological process by further jeopardizing
the potential for neuroplasticity in the cerebral cortex, both directly
and through changes in APP metabolism .
ARF: What's the relative importance of genetics versus environmental
factors, such as increasing age?
Marsel Mesulam: The biological capacity for plasticity decreases
with age, explaining why age is the single most important and universal
risk factor for AD. According to this formulation, the AD of old age may
not be a disease at all but the inevitable manifestation of a failure to
keep up with the increasingly more burdensome work of plasticity. Other
factors such as trisomy 21, the e4 allele of ApoE, estrogen deficiency,
head trauma and the AD-related mutations of APP, PS1 and PS2 accelerate
the time course of the events leading to AD by increasing the burden of
neuroplasticity. The fact that all of these factors operate through a common
downstream mechanism helps to explain how the numerous genotypes of AD cause
an identical clinical and neuropathological disease phenotype. Genetic mutations
do not really cause AD, they simply accelerate the temporal course of events
that lead to plasticity failure and therefore lower the age at which the
pathological process begins to gather momentum. The advanced cognitive and
mnemonic activities of the human brain impose a very high plasticity burden.
The combination of this property with a long life span may endow the human
brain with its unique susceptibility to AD.
ARF: What therapeutic targets do you see as the most promising?
Marsel Mesulam: The first wave of AD therapy has aimed to reverse
the depletion of cortical cholinergic neurotransmission. Subsequent strategies
may aim to inhibit tau polymerization and Aß formation. For reasons
that have been described above, such interventions may not be entirely successful
unless the underlying plasticity failure is also addressed. The proposed
role of plasticity suggests that important insights related to the pathophysiology
and prevention of AD may come from the fields of developmental biology.
One of the most important goals will be to understand the processes that
influence plasticity in the adult human brain and to determine whether their
vulnerability to aging and to the other AD-causing factors can be modified.
ARF: You have mentioned the term "plasticity" as the
unifying feature in AD pathogenesis. Would you summarize what is meant by
the term and how it can cause AD?
Marsel Mesulam: "Neuroplasticity" is a generic term
referring to processes of vital importance for the structural upkeep of
the brain and for the functional adaptation of the organism to the environment.
My hypothesis proposes that the remote initiators of AD may be traced to
factors that erect physiological barriers to the downstream manifestations
of neuroplasticity, and that the NFT and AP represent independent by-products
of initially compensatory but eventually excessive and maladaptive plasticity-related
cellular activity. The exceedingly complex events associated with neuroplasticity
are influenced by multiple genetic and environmental factors. Consequently,
a large number of variables can determine the ease or difficulty with which
the neuroplasticity demands are met and also the time at which perturbations
of neuroplasticity reach the critical threshold and duration needed to trigger
the events that lead to AD.
ARF: How have you seen the field of AD change over the past 30
Marsel Mesulam: From a torpid and esoteric field at the fringes
of neuroscience, to one which is vibrant with excitement and which holds
the key to fundamental questions related to aging and cognition.
ARF: Finally, what advice do you have for young investigators
or graduate students in the field of AD research?
Marsel Mesulam: The best is yet to come.
Mesulam M-M. Neuroplasticity failure in Alzheimer's disease: Bridging the gap between plaques and tangles. Neuron 1999; 24:521-529. Abstract
Marsel Mesulam, M.D., is director of The Cognitive Neurology and Alzheimer's
Disease Center at Northwestern University Medical School, Chicago, IL.