Alzheimer?s disease (AD) is a complex disease developed from multiple pathophysiologic processes with aging, including the dysregulation of immune function and lipid metabolism. Since immune cells and brain fatty acids are modifiable through diet and polyunsaturated fatty acid (PUFA) intake appears to affect the progression of AD, the overall goal of this proposal is to develop one specific n-6 PUFA docosapentaenoic acid (DPAn-6) as a promising new lipid modulator acting on multiple targets in AD. We hypothesize that DPAn-6 modulates TGF? and insuling/IGF signaling pathway to improve immune cellular function and insulin resistance for treating AD pathologies and protecting neurons cognition. DPAn-6 is derived from n-6 precursor linoleic acid. Our rationale is based on our extensive preliminary data, epidemiological and clinical studies. we found that oral DPAn-6 reduced A plaques, neuroinflammation, microgliosis, astrogliosis and apoptosis. In addition, it increases A? autoantibodies, nerve growth factor, BDNF and NPTX2, improving cognitive deficits in old E4FAD mice. High linoleic acid diet inhibited CD4+ T cell brain invasion and cyclooxygenase-2 (COX2), the target of nonsteroidal anti-inflammatory drugs (NSAIDs). Recently, emerging studies report that lower intake n-6 linoleic acid is associated with risk of cognitive decline in aging patients with AD or mild cognitive impairment. However, the underlying therapeutic targets and mechanisms are unknown. This proposal will also fill in a knowledge gap of the impact of n-6 PUFAs on AD. n-6 PUFAs have not been well-studied in AD. N-6 arachidonic acid (ARA) is a substrate for COX1 and COX2 that produces prostaglandins, the important mediators for inflammation. Thus, we pursue two specific aims in this proposal using EFAD and APOE-TR AD mice.
Aim 1 is to determine whether DPAn-6 modulates TGF? /Smad signaling pathway to boost immunity and treat AD neuropathological ?positive? and ?negative? lesions, and thus improving cognitive deficits in APOE AD models.
Aim 2 is to determine the neuroprotective role of DPAn-6 in reducing insulin resistance by modulating insulin/insulin-like growth factor I (IGF-I) signaling pathway. We will also investigate a synergistic effect of a combination of DPAn-6 with n-3 DHA in old EFAD mice. This proposal is innovative and significant because it is based on initial evidence that DPAn-6 modulates TGF? and insulin/IGF signaling pathways to enhance immunity for treating AD pathologies, protecting neurons and improving cognitive deficits in old E4FAD mice. If our aims are achieved, we will develop DPAn-6 as a novel lipid modulator for treating AD that can be readily moved to a clinical trial since it is safe, potent, and can be taken up by brain. Thus, DPAn-6 is a strong but unexplored new candidate for AD intervention. We will also elucidate the protective mechanisms of linoleic acid in epidemiology, in which the LA effect is explained by its metabolite DPAn-6.
This project is built on epidemiological, clinical trials and our novel findings to develop docosapentaenoic acid (DPAn-6) as a new preventive and therapeutic lipid treatment for Alzheimer's disease (AD). Our current findings reveal that oral DPAn-6 rapidly boosts immune function to reduce multiple AD patologies including amyloid (A?) deposits and neuroinflammation, protects neurons and improves cognitive decline in old AD mouse models with APOE4 genes. It is expected that the proposed studies will elucidate the immuno- and neuroprotective mechanisms of the inexpensive and natural product of DPAn-6 for improving public health, which is alreadly proven safe in humans and therefore could quickly be moved to clinical trials.
