Both environmental and genetic factors involved in the disturbance of cholesterol metabolism have been
suggested as risk factors for the development of Alzheimer's disease (AD). Accumulation of cholesterol has
been observed in affected brain areas from AD patients and animals, and it is associated with region-specific
loss of synapses. Elevated brain cholesterol causes cognitive deficits, amyloid-ß (Aß) production and
aggregation, and tau pathology. Despite these observations, the mechanisms that govern brain cholesterol
homeostasis and influence on neurons under AD-related pathological conditions remain elusive. In particular,
the field lacks knowledge on the factors that are involved in the signaling pathways of neuronal cholesterol
metabolism, related to the initiation and development of AD pathology. ATAD3A belongs to a new family of
eukaryotic mitochondrial AAA-ATPases. ATAD3A regulates cholesterol homeostasis and trafficking via an
unknown mechanism at the mitochondria-associated ER membrane (MAM), a specialized subdomain of the
ER that has the features of a lipid raft and is rich in cholesterol and sphingomyelin. Our recent work
demonstrated that ATAD3A, via pathological dimerization, showed a gain-of-function that caused
neurodegeneration in Huntington's disease. We further observed an enhancement of ATAD3A oligomerization
in AD neuronal culture, in AD transgenic mouse brains and in AD patient postmortem hippocampus,
suggesting an aberrant activity of ATAD3A in the pathogenesis of AD. We developed a novel peptide inhibitor
DA1 that binds to ATAD3A to block ATAD3A dimerization. Notably, sustained treatment with DA1 reduced
APP level and amyloid load, attenuated neuro-inflammation and improved short-term spatial memory in 5XFAD
transgenic mice. Further, our proteomic analysis suggests that blocking ATAD3A oligomerization by DA1
treatment mainly influenced the cholesterol metabolic pathway in AD mouse brains. The treatment in AD
transgenic mice improved brain cholesterol turnover and did not affect brain phospholipids levels. Moreover,
we showed that DA1 treatment reduced cholesterol burden and oxidative stress in neuronal cells stably
expressing APP wt or mutant. These findings highlight ATAD3A oligomerization as a previously unidentified
mechanism underlying brain cholesterol disturbance and neurodegeneration in AD. Our central hypothesis is
that ATAD3A oligomerization mediates amyloid pathology, leading to neurodegeneration, by impairment of
brain cholesterol metabolism. The overall goal of this application is to understand ATAD3A aberrant
oligomerization-mediated neuropathology in AD, and to reveal a novel therapeutic target for AD. In Aim 1, we
will determine the impact of ATAD3A oligomerization on brain cholesterol homeostasis, AD pathology and
behavioral deficits in AD mice. In Aim 2, we will determine whether haplosufficiency of ATAD3A in AD mice
restores brain cholesterol homeostasis and reduces AD pathology. In Aim 3, we will dissect the mechanistic
links between ATAD3A oligomerization and disturbance in brain cholesterol homeostasis in AD.