Neuropathologic Changes in Alzheimer's Disease: Potential Targets for Treatment
Gary L. Wenk, MD
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The cognitive symptoms of Alzheimer’s disease (AD) are believed to be caused not only by the
loss of neurons in the cholinergic and glutamatergic neural systems but also by the irregular functioning
of surviving neurons in these 2 systems. Aberrant cholinergic functioning in AD has been linked to
deficits in the neurotransmitter acetylcholine, while AD-related abnormalities in glutamatergic signaling
have been attributed to excitotoxicity caused by the persistent, low-level stimulation of glutamatergic
neurons via the chronic influx of Ca2+ ions through the N-methyl-D-aspartate (NMDA) receptor
calcium channel. Glutamatergic abnormalities in AD can be corrected to some extent by the NMDA
receptor antagonist memantine, an agent whose therapeutic efficacy is believed to be related to its low
to moderate level of affinity for the NMDA receptor calcium channel, a characteristic that allows
memantine to prevent excessive glutamatergic stimulation while still permitting normal glutamatemediated
neurotransmission to take place. Although the mechanism underlying the chronic stimulation
of glutamatergic neurons in AD has yet to be elucidated, one hypothesis is that the characteristic
neuropathologic features of AD—ß-amyloid deposits and neurofibrillary tangles—induce brain inflammation,
which in turn impairs glutamatergic receptor function in such a way that the ability of
these receptors to prevent the influx of Ca2+ in the absence of an appropriate presynaptic signal is
compromised. If this hypothesis is correct, and if it is correct that ß-amyloid deposits and neurofibrillary
tangles arise long before the symptomatic onset of AD, then memantine, with its ability to alleviate
glutamatergic receptor overstimulation, would be expected to provide therapeutic benefits beginning
from the earliest stages of the disease.
J Clin Psychiatry 2006;67(suppl 3):3-7
© Copyright 2006 Physicians Postgraduate Press, Inc.
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