Possible mechanism for resistance to Alzheimer's disease (AD) in mice suggests a new approach to generate a mouse model for sporadic AD and may explain familial resistance to AD in man.
An overproduction of beta-amyloid (A beta) is associated with Alzheimer's disease (AD) and appears to be its primary cause. A model has been recently described which accounts for the overproduction of A beta in sporadic AD, this constituting the majority of all cases of AD. The proposed mechanism suggests the antisense RNA-Mediated generation of a 5'-truncated beta-amyloid precursor protein (beta APP) mRNA encoding a 12-kDa C-terminal fragment of beta APP, the immediate precursor of A beta. In the truncated mRNA, the first AUG codon, which contiguously precedes the A beta-coding segment, becomes the site of translation initiation of a polypeptide that can be further processed to generate A beta, this subsequently being secreted. Among the predictions of the proposed model is that mice and rats do not and indeed cannot develop sporadic AD because they lack the crucial component of the proposed mechanism, namely the ability of the beta APP antisense RNA to self-prime the synthesis of a new sense strand. According to the proposed model, however, mice could be rendered susceptible to AD by mutating the beta APP gene so as to confer self-priming ability on the antisense strand. In contrast to existing mouse models which by design are fundamentally unsuitable for study of the mechanism underlying sporadic AD, the AD pathology of the proposed model would be expected to faithfully reflect the human condition. The availability of such an acutely needed, experimental model would allow investigators to study not only the manifestation of the disease but, most significantly, also the factors triggering it. The proposed mouse model may explain familial resistance to AD in man, provide extremely valuable insights into the etiology of AD, and suggest means for its prevention.
Volloch
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Boston Biomedical Research Institute, Massachusetts 02114, USA.
D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000235:genetics; D001483:Base Sequence; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice / Q000235:genetics*; D008969:Molecular Sequence Data
D016564:Amyloid beta-Protein Precursor; D016375:Antisense Elements (Genetics)