The Effects of Amyloid Precursor Protein on Postsynaptic Composition and Activity

Abstract

The amyloid precursor protein (APP) is cleaved to produce the Alzheimer disease-associated peptide A␤, but the normal functions of uncleaved APP in the brain are unknown. We found that APP was present in the postsynaptic density of central excitatory synapses and coimmunoprecipitated with N-methyl-Daspartate receptors (NMDARs). The presence of APP in the postsynaptic density was supported by the observation that NMDARs regulated trafficking and processing of APP; overexpression of the NR1 subunit increased surface levels of APP, whereas activation of NMDARs decreased surface APP and promoted production of A␤. We transfected APP or APP RNA interference into primary neurons and used electrophysiological techniques to explore the effects of APP on postsynaptic function. Reduction of APP decreased (and overexpression of APP increased) NMDAR whole cell current density and peak amplitude of spontaneous miniature excitatory postsynaptic currents. The increase in NMDAR current by APP was due to specific recruitment of additional NR2B-containing receptors. Consistent with these findings, immunohistochemical experiments demonstrated that APP increased the surface levels and decreased internalization of NR2B subunits. These results demonstrate a novel physiological role of postsynaptic APP in enhancing NMDAR function.Alzheimer disease (AD) 5 is an age-related neurodegenerative disease characterized by the progressive loss of synapses and neurons and by the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are composed predominantly of the A␤ peptide, a 40-or 42-amino acid cleavage product of amyloid precursor protein (APP). APP is a transmembrane protein of unknown function that undergoes extracellular cleavage by one of two activities, ␣-or ␤-secretase, resulting in the formation of large N-terminal extracellular fragments of secreted APP and smaller, membrane-bound C-terminal fragments. If the initial cleavage event occurs via ␤-secretase, then subsequent cleavage of the C-terminal fragment by ␥-secretase results in the production of A␤ (1).Clues to APP function may be gleaned from studies of its different cleavage products or isoforms. Soluble forms of APP have been found to be neurotrophic, and some splice variants have proteinase inhibitor activity (2). The APP intracellular domain may alter gene transcription in conjunction with cytoplasmic proteins (3). In addition, the A␤ peptide has been shown to inhibit glutamate receptor activity (4, 5). However, the function of full-length APP is undefined, and it is likely that full-length APP performs distinct roles from any its cleavage products. One recent study showed that mice lacking APP have impaired development of neuromuscular junctions (6), suggesting an important role for APP in maintaining active synapses. Understanding APP function in central neurons may provide valuable information in generating interventions against the generation of A␤ and thus AD pathogenesis and its accompanying memory loss.Further evidence for a synaptic function of A...

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…The latter may, however, not be entirely dependent on Apoer2 and Vldlr (Chameau et al 2009) and may also involve interactions with APP (Hoe et al 2009). Reelin signaling also regulates dendritic spine morphology (Costa et al 2001;Niu et al 2008;Pujadas et al 2010), which likely involves regulation of actin dynamics and the participation of n-cofilin (Chai et al 2009;Rust et al 2010).…”

“…Numerous independent studies and observations point toward a role for Reelin and ApoE receptors in the formation of neuronal connections (Del Rio et al 1997;Borrell et al 2007) and the generation of dendritic complexity Costa et al 2001;Niu et al 2004;Matsuki et al 2008;Hoe et al 2009). The latter may, however, not be entirely dependent on Apoer2 and Vldlr (Chameau et al 2009) and may also involve interactions with APP (Hoe et al 2009).…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…The presence of mHtt and APP alters the subcellular distribution of NMDAR 18,19 . In mouse models of both diseases, deficits in trafficking mechanisms increase cell surface levels of NR2B and decrease NR2B internalization 18 .…”

“…In mouse models of both diseases, deficits in trafficking mechanisms increase cell surface levels of NR2B and decrease NR2B internalization 18 . Increased levels of NR2B on the cell surface results in enhanced NMDAR currents in mouse models of HD and AD 19 . Both wild type Htt and tau, a neuronal protein that stabilizes microtubules, function in NR2B trafficking as well as the recruitment of kinases to NMDARs at the cell surface.…”

“…Increased extrasynaptic NR2B-containing NMDARs 18,19 Increased phosphorylation of NMDARs 20,22 Affected neurons have defective LTP 25,26 Increased Ca 2+ influx 18 Defects in mitochondrial trafficking 18 …”