AGE-DEPENDENT SUSCEPTIBILITY TO CONDITIONAL PRESENILIN INACTIVATION: A STUDY ON NEURODEGENERATION AND MEMORY IMPAIRMENT

Aging is the most significant non-genetic risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). Presenilins are the active member of the gamma-secretase complex responsible for the intramembrane cleavage of a number of plasma membrane proteins. Although loss-of-function mutations in Presenilin genes (PSEN1/2) cause familial AD, symptoms typically manifest after decades of life, leaving the link between aging and Presenilin dysfunction poorly understood. This study aims to determine if there is a differential susceptibility to Presenilin loss during aging. We used a tamoxifen-inducible conditional knockout mouse model to delete Presenilins in the forebrain at three different stages: one month (young), six months (adult), and twelve months (old) of age. Quantitative analysis six months post-deletion revealed significant neurodegeneration markers, including astrogliosis (GFAP) and microgliosis (Iba1), alongside accumulation of gamma-secretase substrates such as APP-CTF, N-cadherin-CTF, and Neurexin-CTF. Gene expression analysis identified differentially expressed genes with specific signatures emerging from each age group. Furthermore, behavioral assays demonstrated deficits in fear conditioning memory and altered open-field activity. These findings help characterize the molecular and functional consequences of Presenilin loss across the lifespan, providing insights into how the aging process modulates the brain’s vulnerability to the loss of essential AD-associated genes.