Loss of Ataxin-1 Elevates BACE1 Expression and Impairs Axonal Targeting in the Cerebrum

Expansion of CAG trinucleotide repeats in the Ataxin-1 gene (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordinated movement and cognitive functions. ATXN1 is associated with genetic risk for Alzheimer's disease (AD). Here, we show loss of Ataxin-1 potentiates AD pathogenesis. Specifically, knockout of Atxn1 in mice led to increased expression of β-secretase (BACE1) and elevated BACE1-mediated cleavage of the amyloid precursor protein (APP), selectively in AD-vulnerable brain regions. Ataxin-1 depletion exacerbated Aβ plaque deposition and gliosis in AD mice, and impaired hippocampal neurogenesis and axonal targeting. The SCA1-linked CAG repeat number was normal in AD patients. However, in SCA1 mice, aggregation of mutant Ataxin-1 led to BACE1 up-regulation and axon guidance defects in the hippocampal CA2 region. Together, these findings indicate that loss of Ataxin-1 potentiates Aβ pathology, and BACE1 elevation may represent a shared pathogenic mechanism underlying cognitive deficits in SCA1 and AD.