Project Summary/Abstract
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 TGFß
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 Aß plaques, neuroinflammation, microgliosis, astrogliosis and apoptosis. In addition, it increases Aß
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 TGFß /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
TGFß 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.