Aging causes bioenergetic dysfunction in the brain, which is implicated in the pathogenesis
of Alzheimer’s disease (AD). Cardiolipin (CL) is a mitochondrial signature phospholipid that is
essential for membrane structure, bioenergetics, and signaling pathways. Alterations in brain CL
content and acyl compositions are implicated in the pathogenesis of neurodegenerative diseases,
including AD and Parkinson’s disease (PD), but the underlying causes of these defects remain
elusive. Here, we propose to investigate a novel metabolic pathway by which pathological
remodeling of CL promotes the development of AD. This pathway is mediated by the ALCAT1
enzyme, the first acyl-CoA dependent lysocardiolipin acyltransferase previously identified by us.
Our pioneering work in the field has identified ALCAT1 as a key mediator of mitochondrial
dysfunction in age-related metabolic diseases. We show that upregulation of ALCAT1 expression
by reactive oxygen species (ROS) generated by aging promotes mitochondrial dysfunction by
catalyzing pathological remodeling of CL with long chain polyunsaturated fatty acids, such as
docosahexaenoic acid (DHA). Enrichment of DHA renders CL highly sensitive to oxidative
damage by ROS, leading to CL peroxidation and mitochondrial dysfunction. We further show that
ablation or pharmacological inhibition of ALCAT1 successfully mitigates various age-related
metabolic diseases. Remarkably, our preliminary studies also identified a critical role of ALCAT1
in linking aging to the development of AD, which is supported by our findings that: 1) ALCAT1
deficiency significantly extends lifespan in mice; 2) Ablation of ALCAT1 restores cognitive function
and mitigates Aß plague formation in a mouse model of AD; and 3) ALCAT1 deficiency attenuates
neuroinflammation in response to Aß protein aggregation. These exciting findings lead us to test
the hypothesis that CL remodeling by ALCAT1 links aging to the development of AD by
promoting mitochondrial dysfunction (Fig.1), which will be tested by three Specific Aims: AIM
1 will determine whether CL remodeling by ALCAT1 links mitochondrial dysfunction to AD; AIM 2
will identify mechanisms by which ALCAT1 promotes neuroinflammation in AD, and AIM 3 will
provide proof-of-concept studies in targeting ALCAT1 for the treatment of AD.