Distinguishing the Effect of Aging and SIRT1 Manipulation on AD progression with SIRT1 and APP Temporally Regulated Mice Models

Abstract

Alzheimer’s (AD) is a neurodegenerative disease closely linked to aging. However, mouse models with early onset AD are widely utilized, which may cause data deviations since AD normally occurs in aged subjects. In this work, we devised transgenic mouse models with SIRT1, Aβ42 regulated at the first month after birth and 19th months old via Tet-Off/CREer-LoxP systems. Aging/AD/SIRT1-interacted biomarkers were tracked throughout life. Based on the models, the effects of SIRT1, APP, and aging on AD progression are differentiated through temporal manipulation. The possible results of equal or more significant effects of SIRT1 deficiency on AD progression compared to aging hint the presence of pathology distinctly related to AD, which might lie in induced increased neuron death signals and unprotected mitochondria from blocked P53, triggered by loss of SIRT-1 control over apoptotic factors including P53 and FOXO3a. The data obtained from our work can reveal the magnitude of deviation resulting from using early-onset AD models rather than aging mice, hence serving as a reference to possible bias. The raised pathology about SIRT1 and uncontrolled apoptotic factors could serve as a potential target for AD study.