Is Understanding the Biological Function of APP Important in Understanding Alzheimer's Disease? *

Abstract

The presence of mutations around the Aβ sequence in APP provides strong argument for the involvement of APP, and Aβ in particular, in pathogenesis of Alzheimer's disease (AD). In vitro studies demonstrated that Aβ may cause neuronal death, supporting the hypothetical involvement of Aβ in neurodegeneration in AD. However, concentrations of Aβ required for neuronal death are nonphysio-logically high. Nevertheless, the predominant idea in the field is that it is sufficient to postulate Aβ as a major culprit in AD development. The question we pose is whether the potentially important involvement of Aβ precludes the etiological (primary) involvement (not pathological, i.e., secondary) of APP functions. We do not have an adequate answer to this question. Current knowledge about APP functions indicates that APP is critically required for the maintenance of neuronal and synaptic structure and function. Because AD is a disease of neuronal and synaptic deterioration, APP may be involved during the course of AD pathogenesis, perhaps secondarily. To ponder the question whether APP may be etiologically involved in AD, much needs to be learned about APP functions. This article is intended to provide a foundation for this challenging task.