The amyloid that is deposited in the core of the senile plaque in AD is derived from a much larger precursor protein (the beta amyloid precursor protein). Excess amyloid may be formed through an abnormal cleavage (amyloidogenic) pathway in which the larger precursor protein is broken down into abnormal insoluble fragments, which aggregate to form amyloid ( Esch et al., 1990). If this is the case, elucidation of such a pathway and the offending enzyme could allow for the development of protease inhibitors that block amyloidogenesis. Although this appears to be an attractive theoretical approach, it remains unclear whether amyloid plays an important role in the pathogenesis of this disorder and whether decreasing the deposition of amyloid would alter the natural history of the illness or improve symptoms in AD patients.
Although there is no currently effective treatment for AD, some progress has been made in the search for agents that will produce symptomatic improvement in Alzheimer sufferers. The cholinergic hypothesis remains to be proven or refuted by the development of a cholinomimetic agent that can achieve adequate concentrations at the brain receptor site without producing toxic side effects. And, although the ideal cholinomimetic remains to be tested, currently available anticholinesterases indicate that at least a subgroup of patients show a favorable response to augmentation of this system in AD. Future studies will address the exciting possibilities posed by combination neurotransmitter approaches and modulation of brain glutamatergic and peptidergic systems. Finally, the development of peptide trophic factors will provide the opportunity to test the efficacy of trophic agents in improving symptoms and preventing further neuronal degeneration in AD.
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