Synaptic dysfunction is a critical feature of cognitive decline and neurodegeneration associated with Alzheimer's disease (AD). Autosomal dominant mutations in PSEN genes cause familial early-onset AD. Presenilins (PS) form the catalytic center of gamma-secretase, an enzyme responsible for the generation of beta amyloid peptides, which accumulate in the brains of individuals with AD. In addition to intramembranous cleavage of APP, Notch ligands/Notch receptor, and several cell adhesion molecules (CAMs) including cadherins, protocadherins, DCC, ErbB4, ephrin/Eph receptors, nectin-1alpha and syndecan, are also processed by gamma-secretase. Notably, each of these proteins facilitates diverse neuronal functions during embryonic development such as axon guidance, neuronal outgrowth and synaptogenesis. Recently, we reported that loss of PS expression or function in cultured neurons enhances glutamatergic synaptic transmission, synapse formation, and activation of cAMP-dependent signaling cascades. Interestingly, using PS1 M146V knock-in mice we find that expression of FAD-linked mutant also elevates cAMP-dependent signaling in cultured neurons, and leads to increased spine density in CA1 area of hippocampus. Analysis of DCC (the netrin receptor) processing revealed that lack of gamma-secretase cleavage increases neurite outgrowth and cAMP-dependent signaling, illustrating a novel function for PS wherein cleavage by gamma-secretase terminates intracellular signaling cascades associated with certain CAM substrates. Taken together, we hypothesize that gamma-secretase processing of certain CAMs regulates signaling cascades that play pivotal roles in synapse formation, synaptic transmission and plasticity. We also hypothesize that FAD-linked PS1 variants promote AD pathogenesis by influencing Abeta generation as well as proteolysis of certain CAMs that are important for synaptic function.
The specific aims of this investigation are to examine the influence of PS-dependent proteolysis of CAMs: 1) on cellular function, 2) on synapse formation, and 3) on cellular substrates of memory. Using PS1 null embryos, PS1 M146V knock-in mice, and cultured cell systems we propose to perform electrophysiological, biochemical and imaging studies to investigate how PS-dependent proteolysis of CAMs influences synaptic functions. In particular, we will focus our studies on the synaptic influence of APP, DCC and N-cadherin in normal and pathological conditions because of their known association with the pathogenesis of AD, synapse formation and signaling pathways related to synaptic functions. We are extremely confident that our complementary approaches outlined in our proposal will provide important mechanistic insights into the role of PS in health and disease.
|Andrew, Robert J; Fernandez, Celia G; Stanley, Molly et al. (2017) Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease. Proc Natl Acad Sci U S A 114:E9665-E9674|
|Deyts, Carole; Thinakaran, Gopal; Parent, Angèle T (2016) APP Receptor? To Be or Not To Be. Trends Pharmacol Sci 37:390-411|
|Deyts, Carole; Clutter, Mary; Herrera, Stacy et al. (2016) Loss of presenilin function is associated with a selective gain of APP function. Elife 5:|
|Buggia-Prévot, Virginie; Fernandez, Celia G; Udayar, Vinod et al. (2013) A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease A? production. Cell Rep 5:1552-63|
|Deyts, Carole; Vetrivel, Kulandaivelu S; Das, Shibandri et al. (2012) Novel GýýS-protein signaling associated with membrane-tethered amyloid precursor protein intracellular domain. J Neurosci 32:1714-29|
|Gong, Ping; Roseman, Jelita; Fernandez, Celia G et al. (2011) Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice. Mol Neurodegener 6:87|
|Parent, Angele T; Thinakaran, Gopal (2010) Modeling presenilin-dependent familial Alzheimer's disease: emphasis on presenilin substrate-mediated signaling and synaptic function. Int J Alzheimers Dis 2010:|
|Meckler, Xavier; Roseman, Jelita; Das, Pritam et al. (2010) Reduced Alzheimer's disease ýý-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin. J Neurosci 30:16160-9|
|Gong, Ping; Vetrivel, Kulandaivelu S; Nguyen, Phuong D et al. (2010) Mutation analysis of the presenilin 1 N-terminal domain reveals a broad spectrum of gamma-secretase activity toward amyloid precursor protein and other substrates. J Biol Chem 285:38042-52|
|Vetrivel, Kulandaivelu S; Kodam, Anitha; Gong, Ping et al. (2008) Localization and regional distribution of p23/TMP21 in the brain. Neurobiol Dis 32:37-49|