A role for the β-amyloid precursor protein in memory?

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Abstract
Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the most common type of dementia occurring in mid-to-late life. Morphological and neurochemical studies have established that AD is associated with selective lesions of neuronal circuits in the neocortex, hippocampus, and basal forebrain cholinergic system. The principal consequence of these lesions is a diminution of synaptic inputs in these regions of the brain, leading to memory and attentional impairments (1). The principal neuropathological hallmarks of AD are the presence of neurofibrillary tangles, intracytoplasmic filaments of hyperphosphorylated forms of tau, and senile plaques, comprised of dystrophic neurites (abnormal neuronal processes) displayed in proximity to deposits of 39- to 42-aa β-amyloid (Aβ) peptides (2, 3). Aβ fibrillar aggregates act as a nidus for subsequent deposits of other proteins (4) and by mechanisms not presently understood and appear to be toxic to nerve cells (5). The mechanisms by which Aβ, tau, and associated polypeptides impact on the pathophysiology of AD are being actively investigated, with the underlying assumption that these molecular targets might offer opportunities for novel therapeutic interventions. Much less is understood about the complexities underlying the cognitive and attentional deficits of patients with AD. It is to this arena that we are offered a tantalizing insight. In this issue of the Proceedings , Mezaine and colleagues (6) report that in behavioral paradigms, a secreted form of the β-amyloid precursor protein (APPsα) has memory-enhancing effects in normal and amnestic mice. The data are interpreted to suggest that APPsα plays an important role in the formation and/or consolidation of memory. How compelling is this information and by what physiological mechanism(s) might these effects be facilitated? To discuss the potential significance of the new findings, it is useful to put into perspective our current understanding of the biology and function of …