Transient defects in Abeta catabolism in the etiology of sporadic Alzheimer disease

University Of California-Irvine, Irvine CA

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Abstract

PROJECT SUMMARY/ABSTRACT 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 ß-peptide (Aß), thus strongly implicating Aß in the pathogenesis fAD, but there is considerable uncertainty about the role of Aß 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 Aß (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 Aß portion of murine APP. The resulting animals, dubbed APPKI-hAßwt mice, express wild-type human Aß 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 Aß 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? Aß 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 Aß. However, it remains to be established whether transient increases in human Aß 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 Aß/APP. Accordingly, the objective of the present proposal is to use the APPKI-hAßwt line to investigate whether a single transient elevation in Aß 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 Aß levels using highly selective inhibitors of two Aß-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.