Genetics and function of proteins involved in neurodegeneration (APP, presenilin, tau)
Neurodegenerative disorders are characterized by a chronic, progressive, and selective loss of neurons in cognitive, sensory and motor systems. Alzheimer disease (AD), the most common cause of dementia in the aged, results from severe neuronal loss and synaptic abnormalities in the hippocampus and neocortex and is characterized by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs) in specific brain areas. Most AD cases are classified as “sporadic” because they lack an obvious genetic etiology. A small percent of all cases however, segregates within families (FAD) suggesting genetic etiologies. Most genetic mutations linked to FAD map on three genes: the amyloid precursor protein (APP) on chromosome 21, presenilin1 (PS1) on chromosomes 14 and presenilin2 (PS2) on chromosome 1. There are more than 150 PS1 mutations linked to FAD while about 20 such mutations are found in APP and 10 in PS2. Proteolytic processing of APP results in the production of Aβ peptides that aggregate to form the amyloid depositions that define AD. The mechanism by which APP and PS mutants promote neuronal cell death and AD is not clear. There is evidence, however, that the FAD mutations interfere with biological function of proteins including interference with signal transduction pathways and gene expression.
To understand the consequences of the FAD mutations on neuurodegeneration we study the genetics, molecular biology, and function of the wild type and mutant PSs and APP. PSs are components of the γ-secretase system that regulates proteolytic processing of cell surface proteins including APP, cadherins, Notch1R, EphB receptor and ephrinB protein. PS1 controls proteolytic processing of these factors a process that produces intracellular peptides with signal transduction functions. Interestingly, we obtained evidence that PS FAD mutants inhibit the PS/γ-secretase-catalyzed cleavage of cell surface receptors. PS1 concentrates at synaptic contacts where it forms complexes with brain N-cadherin, an important component of synaptic structures. The PS1-dependent cleavage of N-cadherin is regulated by NMDA receptor activity and the resulting peptide promotes degradation of CBP thus regulating CREB/CBP-dependent gene expression (Marambaud et al., 2003). Recently we reported that PS1 regulates processing of the neuronal EphB2 receptor-ephrinB ligand bidirectional signaling system that regulates synapse formation and function. FAD mutations interfere with the processing of the EphB-ephrinB receptor system. Thus, FAD mutations may interfere with the production of signal transduction peptides and gene expression pathways (Marambaud et al., 2003; Georgakopoulos et al., 2006; Litterst et al., 2007; Xu et al., 2009).
We also found that PS1 regulates the PI3K/Akt cell survival pathway. This is a new function of PS1 with potential applications in AD because this pathway plays central roles in neuronal survival (Baki et al., 2004 and 2008). To answer our questions we use in vitro gene expression systems, neuronal cell survival assays and transgenic FAD mouse models expressing PS1 and APP mutant proteins.
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