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UAMS
Institute on
Aging
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Synopsis of Neuropathology Research
Supported by the
Neuropathology Core
Research performed at UAMS over the past 15 years has
highlighted the role of the glial inflammatory processes in the
neuropathological changes of Alzheimer's Disease.
We have shown that
activated
microglia, overexpressing
the key immunomodulatory cytokine interleukin-1, are present in amyloid
plaques in Alzheimer's Disease. These microglia wax and wane in concert
with plaque progression and neuritic pathology in
different plaque
stages.
A second component of Alzheimer amyloid plaques are
activated astrocytes
overexpressing the neurotropic cytokine S100beta. Like activated microglia,
the number of these astrocytes waxes and wanes with plaque progression and
especially with neuritic pathology, suggesting a role for S100beta in the
neuritic damage that occurs in these plaques. These changes are
accompanied by evidence of progressive neuronal injury and
loss,
suggesting that plaque-associated neuronal toxicity, arising from local
cytokine overexpression, is an important cause of neurological decline in
Alzheimer's Disease. This work has greatly increased our understanding of
the pathophysiology of amyloid plaques in Alzheimer's Disease, and of the
driving forces underlying plaque progression. We have also shown that
activated microglia and astrocytes are found in association with the other
key neuropathological feature of Alzheimer's Disease, the
neurofibrillary
tangle.
This work has advanced the hypothesis that chronic
activation of glial inflammatory processes- arising from genetic or
environmental insults to neurons and accompanied by chronic elaboration of
neuroactive glia-derived cytokines and other proteins, sets in motion a
cytokine cycle of cellular and molecular eventswith neurodegenerative
consequences. In this cycle, interleukin-1 is a key initiating and
coordinating agent: Interleukin-1 i) promotes neuronal synthesis and
processing of the beta-amyloid precursor protein- thus favoring continuing
deposition of beta-amyloid-- and ii) activates astrocytesand promotes
astrocytic synthesis and release of a number of inflammatory and
neuroactive molecules. One of these-- S100beta-- is a neurite growth
promoting cytokine that, in turn, stresses neurons and through its trophic
actions and fosters neuronal cell dysfunction and death by raising
intraneuronal free calcium concentrations. Neuronal injury arising from
these cytokine-induced neuronal insults can further activate microglia
with further overexpression of interleukin-1, thus producing feedback
amplification and self-propagation of this cytokine cycle. Additional
feedback amplification is provided through other elements of the cycle.
Chronic propagation of this cytokine cycle represents a possible mechanism
for progression of neurodegenerative changes culminating in Alzheimer's
Disease. This work is described in more detail in the
original
publications, and in a number of journal reviews and
book chapters.
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