Merin John

Alzheimer disease(AD) is a neurodegenerative disease marked by progressive loss of cognitive function. AD risk has complex genetic influences, with ATAXIN-1(ATXN1) being one of the genes identified to increase risk of late-onset AD. Mutations in ATXN1 cause Spinocerebellar Ataxia Type-1(SCA1), with most patients experiencing partial loss of normal ATXN1. The beta-secretase-1 enzyme(BACE1) plays a large role in the amyloid precursor protein(APP) processing pathway which leads to the pathogenesis of AD. Previous studies in mice have shown that full loss of Atxn1 increases BACE1 activity by upregulating its transcription, although the effect of a partial loss of Atxn1 is unknown. My project aims to determine how 50% loss of Atxn1(Atxn1 +/-) impacts BACE1 activity in the brain. I used western blotting and immunohistochemistry to quantify BACE1 and APP levels in AD vulnerable brain regions of Atxn1 wild-type(Atxn1+/+) and Atxn1 heterozygous(Atxn1+/-) mice. I hypothesized that BACE1 levels would increase in Atxn1 heterozygous mice, and APP levels would decrease. My results show that BACE1 levels trend higher in Atxn1 heterozygous mice in the cortex, cerebellum, and hippocampus, but that APP levels did not show a consistent trend. These results suggest that BACE1 expression may be increased in Atxn1 heterozygous mice, supporting the role of ATXN1 in regulating BACE1 expression. Surprisingly, APP protein levels did not correlate with BACE1 expression in the hippocampus, indicating that Atxn1 may have other regulatory roles in the hippocampus. This work may be strengthened with further study increasing sample sizes, as well as comparing BACE1 mRNA levels in wild-type and heterozygous mice.