Neuropathologic changes in Alzheimer's disease: potential targets for treatment

Abstract

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 Ca(2+) 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 glutamate-mediated 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 -- beta-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 Ca(2+) in the absence of an appropriate presynaptic signal is compromised. If this hypothesis is correct, and if it is correct that beta-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.