Growing evidence indicates that Alzheimer's disease (AD) is associated with profound changes in the metabolism of lipids and that these changes, in turn, may be responsible for the perturbation of molecular pathways underlying synaptic dysfunction and cognitive decline. In this proposal, we investigate the link between amyloid beta (Abeta) and phosphatidic acid (PtdOH), a key signaling phospholipid that controls multiple cellular processes. We have found that a treatment of cultured neurons with soluble Abeta oligomers increases PtdOH levels without marked effects on cell viability. Because the phospholipase D (PLD) pathway is a primary source of PtdOH, we have focused on this family of lipid enzymes. Accordingly, treatment of cultured neurons and neuroblastoma cells with Abeta42 oligomers as well as expression ofthe Swedish mutant of APP (swAPP) lead to a significant increase in PLD activity. To genetically test for the relevance of the PLD pathway in AD, we have generated mice harboring a conditional deletion of the Pld2 gene. Our preliminary results indicate that Pld2 ablation suppresses the synaptic-impairing action of Abeta in hippocampal slices, suggesting that it confers protection against the cytotoxic petide. Furthermore, Pld2 knockout cortical neurons secrete lower amounts of AP40 and AP42, indicating that PLD2 also modulates the processing of amyloid precursor protein (APP). Stirkingly, our behavioral analysis shows that contextual learning is improved in a transgenic mouse model of AD (swAPP) that either lacks one copy (swAPP/Pld2+/-) or two copies (swAPP/Pld2-/-) of Pld2. Altogether, our findings suggest a hypothesis whereby PtdOH dyshomeostasis may be a key manifestation in AD, where it may account for aberrant processing of APP and participate to the neurotoxic effects of Abeta in neurons.
The specific aims ofthis application will be: (i) to further characterize biochemical changes in PtdOH metabolism and PLD activity downstream of Abeta and swAPP expression;(ii) to investigate the processing of APP upon ablation ofthe Pld2 gene in cultured neurons as well as in vivo;and (iii) to test whether ablation of Pld2 ameliorates synaptic dysfunction and learning deficits in the swAPP mouse model.

Public Health Relevance

AD is the most common form of late onset dementia. Because Amyloid Precursor Protein plays a fundamental role in this disorder, understanding the molecular mechanisms, and lipid changes in particular, which regulate the processing of this protein as well as signaling downstream of amyloid beta is of critical importance to prevent AD-linked synaptic dysfunction and cognitive decline.

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Besser, Lilah M; Alosco, Michael L; Ramirez Gomez, Liliana et al. (2016) Late-Life Vascular Risk Factors and Alzheimer Disease Neuropathology in Individuals with Normal Cognition. J Neuropathol Exp Neurol 75:955-962
Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2016) Neuropsychiatric symptoms and Apolipoprotein E: Associations with eventual Alzheimer's disease development. Arch Gerontol Geriatr 65:231-8
John, Samantha E; Gurnani, Ashita S; Bussell, Cara et al. (2016) The effectiveness and unique contribution of neuropsychological tests and the δ latent phenotype in the differential diagnosis of dementia in the uniform data set. Neuropsychology 30:946-960
Hur, Jang Ho; Park, Shi-Young; Dall'Armi, Claudia et al. (2016) Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect. Sci Rep 6:39170
Bonham, Luke W; Geier, Ethan G; Fan, Chun C et al. (2016) Age-dependent effects of APOE ε4 in preclinical Alzheimer's disease. Ann Clin Transl Neurol 3:668-77
Ting, Simon Kang Seng; Hao, Ying; Chia, Pei Shi et al. (2016) Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease. Sci Rep 6:20858
Fischer, Corinne E; Qian, Winnie; Schweizer, Tom A et al. (2016) Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer's Disease. J Alzheimers Dis 50:283-95
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
McCutcheon, Sarah T; Han, Dingfen; Troncoso, Juan et al. (2016) Clinicopathological correlates of depression in early Alzheimer's disease in the NACC. Int J Geriatr Psychiatry 31:1301-1311
Ebbert, Mark T W; Boehme, Kevin L; Wadsworth, Mark E et al. (2016) Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Alzheimers Dement 12:121-9

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