Disrupted Lipid Metabolism in Alzheimer's Disease - PROJECT SUMMARY
Alzheimer’s disease (AD) is the most prevalent form of dementia affecting approximately 50 million people
worldwide. Large volumes of clinical evidence have revealed alterations in lipid metabolism emerging in
early stages of the disease. Moreover, a variety of lipid-related genes and peripheral lipid abnormalities
have been identified as significant AD risk modifiers. However, the precise mechanisms by which disrupted
lipid metabolism is initiated, and how it subsequently contributes to AD pathologies, remain elusive. As the
essential building blocks for most lipid species, the homeostasis of fatty acid (FA) is key to the composition
and functionality of brain lipids. While the synthesis, transport and utilization of FAs involve all brain cell
types, the degradation of FAs occurs predominantly in astrocytes via mitochondrial FA β-oxidation (FAO)
and oxidative phosphorylation (OxPhos). This unique metabolic feature of astrocytes, along with the early
occurrence of their reactive transformation in AD brains, strongly suggests a vital role of astrocytes in AD-
associated lipid dyshomeostasis and raises the question as to whether and how disrupted astrocytic FA
degradation promotes disease onset and progression. Our recent work demonstrates that loss of FA
degradation by astrocytic mitochondria is sufficient to trigger lipid droplet accumulation and reactive
astrogliosis followed by progressive, AD-resembling neuroinflammation, neurodegeneration and cognitive
impairment. We further reported that reduced astrocytic FA degradation occurs in early stages of an
amyloidosis model of AD. Research proposed herein will test our hypothesis that β-amyloid (Aβ)-driven
metabolic reprogramming of astrocytes impairs FA degradation and triggers lipid dyshomeostasis and astrocyte
reactivity, which consequently drive or exacerbate proteinopathies (Aβ and tau) and other AD pathologies. We
further hypothesize that enhancing astrocytic FA degradation alleviates these AD hallmarks and cognitive deficit
by restoring brain lipid homeostasis and suppressing detrimental transformation of astrocyte. We will first
determine when, where, and how early amyloid pathology metabolically reprograms astrocytes towards AD-
associated transformation using an amyloidosis model of AD. Utilizing our validated model of astrocytic FA
degradation deficit, we will determine the mechanisms by which impaired astrocytic lipid degradation drives or
exacerbates AD pathologies. Lastly, we will test whether selective enhancement of astrocytic FA degradation
can ameliorate lipid dyshomeostasis, neuroinflammation, AD proteinopathies, and cognitive impairment in both
amyloid and tau models. Projected outcomes from this research will test the early, and potentially central, role
of lipid dysregulation and astrocyte reactivity in driving AD pathologies. Translationally, this research could also
pave the way to novel astrocyte-specific AD therapeutics by sustaining or restoring efficient lipid turnover in
the degenerating brain.
