Thursday, November 21, 2024
11/21/2024
Alzheimer’s disease (AD), a major form of dementia, starts with synaptic dysfunction and progresses to massive neurodegeneration. Mutations of amyloid precursor protein (APP) that increase amyloid plaque (one of the two AD hallmarks) are found in the very rare familial AD (fAD, a.k.a. early-onset AD or EOAD). The discoveries of mutations in PSEN1/2 that make amyloid peptides from APP reinforce the amyloid hypothesis, positing that A (-amyloid peptide) aggregation causes synaptic dysfunction and neurodegeneration. There are many other risk factors have been discovered through genomic screen of thousands of patients with sporadic AD (sAD), highlighting that the cause of AD is likely multifactorial. Early studies about APP led to various theories about its functions, ranging from neurodevelopment to apoptosis. But the link between APP and AD remains elusive other than A. Very recently, our work in mouse neurons led to an intriguing discovery – APP and cholesterol (Chol) are inversely correlated in the plasmalemma of presynaptic terminals. Moreover, point mutations within APP’s Chol-interactive motif (CIM) causes APP increase and Chol decrease at the plasmalemma of axon terminals. Chronically, those mutations led to abnormality in synaptic vesicles (SVs), swollen synapses, disintegrated axons and tau hyperphosphorylation. Hence, we postulate that APP regulates presynaptic Chol and that APP mutations triggers neurodegeneration by disrupting neuronal Chol homeostasis. In fact, a lot of evidence supports a close tie between Chol and AD: (1) ApoE4, the highest genetic risk factor for sAD is an isoform of Apolipoprotein E and it often accompany with abnormal lipid metabolism in the brain; (2) brain Chol metabolism declines during aging, the primary risk factor for AD; (3) mutations found in Niemann-Pick Type C1 disease interferes with Chol supply to plasmalemma and cause “juvenile AD” phenotype in the mouse model; (4) APP intracellular domain cleaved off by -secretase serves as a suppressor for the expression of lipoprotein receptor; (5) both APP and Chol are concentrated at axon terminals and crucial for synaptic plasticity, the biological basis for learning and memory. Here, we will test the hypothesis that mutations affecting APP distribution, trafficking, and interaction with Chol triggers synaptic dysfunction and neurodegeneration via disrupted presynaptic Chol homeostasis. To do so, we will use human neurons differentiated from induced pluripotent cells (hiNs) for better clinical relevance. Methodologically, we will employ new imaging tools and electrophysiological recording] to systematically investigate APP, Chol, synaptic transmission, plasticity and cell pathology. If successful, this project will provide new insights about APP’s intrinsic function, the importance of presynaptic Chol, and, more importantly, the cause of AD, which will lend a hand to new therapeutic strategies for AD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
