While the prevalence of Alzheimer's disease (AD) is rapidly progressing throughout the world, the mechanism of development of this most common form of late-onset dementia remains elusive. Growing evidence indicates that cerebral accumulation of amyloid-beta peptide (Abeta) mediate many aspects of AD pathogenesis. Abeta is produced by sequential cleavage of Alzheimer's Precursor Protein (APP) by beta-secretase and gamma-secretase. Derangement of APP processing leads to cellular oxidation, excitotoxicity, inflammation, and in several instances, tau hyperphosphorylation. Over time global neurological insults result in synaptic dysfunction and neuronal death, thereby causing cognitive and behavioral abnormalities. Thus, understanding the regulation of the cellular fate of APP, determined by its trafficking and processing, is of paramount importance. It is known that APP traffics through the biosynthetic pathway to reach the cell surface, from where it is internalized to the endosomal compartment, the main site of amyloidogenesis. The goal of this proposal is to understand the role of the phospholipase D (PLD) pathway in the trafficking and processing of APP. Two isoforms of this enzyme, PLD1 and 2, catalyze the breakdown of phosphatidylcholine to phosphatidic acid (PA). PA is a second messenger that drives vesicular trafficking processes such as Golgi transport, endocytosis, and exocytosis. Previous work from others reveals that PLD1 overexpression affects the trafficking of APP as well as presenilin, the catalytic subunit of the gamma-secretase complex. Our unpublished studies using a murine genetic ablation approach indicate that PLD1 partially colocalizes with an endosomal pool of APP and that genetic ablation of PLD2 is protective in the context of mouse models of AD. Thus, we hypothesize that the PLD family members may be primary regulators of the trafficking and processing of APP.
The Specific Aims of this proposal to assess the role of PLD1 in AD pathogenesis will be: (i) to characterize the trafficking pattern of APP in primary fibroblasts and cortical neurons lacking PLD1, (ii) to test whether genetic ablation of PLD1 alters the processing of APP in cultured systems as well as in transgenic models of AD, and (iii) to assess whether ablation of PLD1 ameliorates synaptic and cognitive functions in these mouse models. In support of the mission of reducing the burden of neurological disease, we anticipate that our studies will lead to significant advances in our understanding of molecular pathogenesis of AD for the purpose of the identification of novel therapeutic targets for this disorder.
Alzheimer's disease, the most common neurodegenerative disorder which affects 5.3 million Americans1, is a sporadic condition that can be occasionally inherited and develops over time through small pathological changes in the brain of an effected individual. This investigation will use a mammalian genetic ablation model to study how changes in cell membranes mediated by phospholipase D1 affect the cellular fate of Alzheimer's precursor protein (APP). The goal of this research is to identify regulatory elements of cellular pathways that direct APP so that they may be targeted by therapies designed to lessen the societal and individual burden of this disease.
| Morel, Etienne; Chamoun, Zeina; Lasiecka, Zofia M et al. (2013) Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun 4:2250 |
