Mechanisms underlying Alzheimer's disease (AD) has progressed based on the 'amyloid cascade hypothesis', which posits that A? deposits primarily contribute to neuronal death and neurofibrillary tangle (NFT) formation. Animal modeling studies support the idea that A? can trigger NFT formation. Therefore, current AD therapy driven by the amyloid hypothesis mostly focuses on reducing cerebral A? levels. However, recent studies showed that A?40 had anti-amyloidogenic effect in vivo thereby suggesting that amyloid therapy targeting A? without any selectivity of single A? species should be approached with caution. We hypothesize that A?40 can attenuate memory impairment and may therefore represent a protective species of A?. To address this hypothesis, we will test the effect of secreted A? on the cognitive function in the rTg4510 mouse model which develops NFTs, neuronal loss and memory impairment in an age-dependent manner. The rTg4510 mice have several advantages such as rapid progression of tau pathology, strong tau expression in a forebrain-specific pattern, and conditional expression of tau. To determine the impact of A?40 in the mouse brain, we will drive A? production using the method of brain-wide transduction of neurons by administering adeno-associated virus (AAV) intracerebroventricularly (i.c.v.) to newborn pups. An AAV construct expressing A?40 or A?42 peptide fused to the C-terminal end of the BRI protein will be utilized so that we can focus our studies specifically on the A?40 or A?42 peptides. This method will allow us to avoid confounding, albeit potentially interesting, effects arising from APP processing derivatives and the subcellular localization of processing. The rTg4510 mice with or without A? peptide expression will be analyzed for cognitive function, brain biochemistry, and neuropathology. If our hypothesis is proven correct, the strategies of selective increases in A?40 levels may be effective at reducing the risk for development of AD. In any case, the results will provide important clues to answer whether A? peptides act to deteriorate cognitive function.
During the last 20 years, our understanding of mechanisms underlying Alzheimer's disease, a progressive neurological disorder with memory loss and confusion, has progressed based on the amyloid hypothesis. Recent study showed that A?40 may have an anti-amyloidogenic effect in vivo suggesting that amyloid therapy targeting A? without any selectivity of specific A? species should be approached with caution. Here, we hypothesize that A?40 may attenuate memory impairment and the strategies of selectively increasing A?40 levels may be effective at reducing the risk for development of AD.
