Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in loss of neurons and synapses. The dementia associated with AD is devastating for families and poses an increasing social and economic burden as our population ages. Currently there are no drugs available that can revert or even slow disease progression. Brains from human patients with AD exhibit two defining pathological changes: 1) Accumulation of extracellular amyloid plaques which are composed of amyloid beta (Aß), and; 2) accumulation of intracellular neurofibrillary tangles which are made up of hyperphosphorylated tau (pTau) protein. These changes are thought to be toxic and contribute to the devastating neurodegeneration that occurs in AD. Recent developments in disease modeling using human induced pluripotent stem cells (hiPSCs) have allowed for modeling of Alzheimer’s disease in human neurons in a dish. We can measure Aß and pTau levels in these hiPSC derived neurons allowing us to study how the levels of these proteins become dysregulated in AD.

Genetic, biochemical, pharmacological, and epidemiological data suggest a role for cholesterol in AD pathogenesis. Recent studies have shown that amyloid precursor protein (APP), the precursor to Aß contains a cholesterol binding site. We use cholesterol lowering drugs, CRISPR/CAS9 genome editing, and fluorescent complementation assays to study how cholesterol levels and mutations that abolish APP-Cholesterol binding influence Aß and pTau burden. Our data indicate that cholesterol metabolism influences levels of these toxic proteins. We also show that APP can influence cholesterol homeostasis by regulating transport of cholesterol between different cell types in the brain. Our work sheds light on a pathway which unites the variety of genetic and environmental factors that contribute to AD risk. Targeting cholesterol metabolic pathways may be a promising approach in the search for drugs which can treat or prevent AD.