The specific pathogenic mechanisms causing Alzheimer disease (AD) are known with certainty only for extremely rare forms of the disease attributable to genetic mutations, known as famial AD (fAD). However, for the vast majority of cases, known as sporadic AD (sAD), the specific cause(s) remain obscure. fAD-linked mutations are known to perturb the processing and/or aggregation of the amyloid -peptide (A), thus strongly implicating A in the pathogenesis fAD, but there is considerable uncertainty about the role of A in the etiology of sAD. A major impediment to the resolution of this question has been the lack of animal models that faithfully recapitulate the physiological milieu from which sAD emerges. Most existing AD mouse models express superphysiological levels of the amyloid precursor protein (APP) harboring fAD-linked mutations and under the control of heterologous promoters. Although these models successfully reproduce amyloid deposits and other associated features of the disease, they are not useful for uncovering the specific mechanisms that trigger amyloidosis in the absence of fAD mutations or hyperphysiological levels of A (and other APP metabolites), mechanisms that by definition must be operative in sAD. To address these limitations, we have developed a novel mouse model wherein gene targeting was used to ?humanize? the A portion of murine APP. The resulting animals, dubbed APPKI-hAwt mice, express wild-type human A at physiological levels under the control of the endogenous murine App promoter. As is true for normal humans, these animals develop diffuse deposits of human A in an age-dependent manner, but do not form the dense-core amyloid plaques characterizing AD. Accordingly, these mice are ideal for investigating the pathophysiological mechanisms responsible for transforming ?normal? A deposition to the pathological variety that occurs in AD. Multiple forms of acute brain injury, such as head trauma and ischemia/hypoperfusion, are established risk factors for sAD, and these are known to result in transient elevations in A. However, it remains to be established whether transient increases in human A per se are responsible for triggering AD-type pathology, rather than myriad other sequelae resulting from brain trauma, in the absence of fAD mutations or overexpression of A/APP. Accordingly, the objective of the present proposal is to use the APPKI-hAwt line to investigate whether a single transient elevation in A early in life is sufficient to produce AD-type pathology later in life. To investigate this question cleanly, we will employ a novel pharmacological approach wherein we increase A levels using highly selective inhibitors of two A-degrading proteases?neprilysin and insulin- degrading enzyme, as well as a broad-spectrum metalloprotease inhibitor. The successful completion of this project is expected to yield new insights into the specific molecular mechanisms underlying the initiation of sAD, which could facilitate the development of acute interventions to mitigate AD risk following brain injury.
This project will conduct basic research into the causes of Alzheimer's disease (AD), specifically those forms of AD that are not attributable to specific genetic causes. We will use a novel animal model that expresses the human form of a protein known as the amyloid -protein (A), which is strongly implicated in the disease, to test whether transient increases in the levels of A early in life are sufficient to trigger AD-like pathology later in life. Because increases in A are a common consequence of several forms of brain trauma, which are themselves known risk factors for AD, this work is expected to improve our understanding of the origins of AD, and may lead to the development of innovative therapies and/or improved methods for the early detection of this devastating disease.
