Role of Glutamate and GABA in a mouse model expressing mutant human APP in the absence of NPC1 protein
Date
Author
Institution
Degree Level
Degree
Department
Supervisor / Co-Supervisor and Their Department(s)
Examining Committee Member(s) and Their Department(s)
Citation for Previous Publication
Link to Related Item
Abstract
Cholesterol plays a critical role in Alzheimer’s disease (AD) pathogenesis, but the underlying mechanisms remain unclear. To address this issue we have generated a line of ANPC transgenic mice that overexpress mutant-human amyloid precursor protein in the absence of cholesterol transporting Niemann Pick-type C1 protein. These mice display accelerated AD-related pathology compared to age-matched littermates. To define significance of GABA and glutamate in AD, we evaluated alterations of these systems in ANPC mice at different age groups. The levels of glutamate and GABA were not unaltered in ANPC mice compared to other lines. However, levels of vesicular glutamate transporter 1 (i.e. VGLUT1), and expression of VGLUT1 and VGLUT2 appeared to be decreased in ANPC mice. The levels/distribution of glutamic acid decarboxylase 67 (i.e. GAD67) but not GAD65 were also decreased in the cerebellum of ANPC mice. Thus, cholesterol accumulation influences AD-related pathology and triggers subtle alterations in brain neurotransmitter system.