Cell Surface amyloid β-protein precursor colocalizes with β1 integrins at substrate contact sites in neural cells

Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/1997; 17(3):1004-10.
Source: PubMed


Amyloid beta-protein (A beta), the principal constituent of the senile plaques seen in Alzheimer's disease (AD), is derived by proteolysis from the beta-amyloid precursor protein (beta PP). The distribution and trafficking of cell surface beta PP are of particular interest because some of these molecules are direct precursors of secreted A beta and because the localization of beta PP at the cell surface may be related directly to its physiological functions. Recently, we reported that, in cultured hippocampal neurons, cell surface beta PP is preferentially expressed on axons in a striking discontinuous pattern. In this study, we describe the colocalization of cell surface beta PP and integrins in primary cultured cells. In rat hippocampal neurons, cell surface beta PP was colocalized selectively with alpha 1 beta 1 and alpha 5 beta 1 integrin heterodimers at these characteristic segmental locations. In rat cortical astrocytes, both cell surface beta PP and beta 1 integrin were located at the cell periphery in the "spreading" stage shortly after plating. In "flattened" astrocytes cultured for several days, beta PP was found in punctate deposits called point contacts. In these sites, beta PP was colocalized with alpha 1 beta 1, but not with alpha 5 beta 1 integrin heterodimers, the latter of which were situated at focal contact sites. In both neurons and astrocytes examined after shearing, clathrin and alpha-adaptin were colocalized with beta PP on the surface that directly contacts the substratum. These results are consistent with the putative role of beta PP in cell adhesion and suggests that beta PP either interacts with selected integrins or shares similar cellular machinery to promote cell adhesion.

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    • "One such BACE1 substrate is APP, which has been hypothesized to play a role in neuroprotection [29], cell adhesion [99, 117], neurite outgrowth (reviewed in [104]), synapse formation or maintenance [80], as well as regulating synaptic transmission [43]. APP is transported to the neuronal terminal [52, 97] where it is likely processed by BACE1 and γ-secretase to generate secreted APP ectodomain (APPsβ), APP C-terminal fragment (β-CTF), and Aβ [40, 64, 96, 106, 118]. "
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    ABSTRACT: β-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the β-secretase that initiates Aβ production in Alzheimer’s disease (AD). BACE1 levels are increased in AD, which could contribute to pathogenesis, yet the mechanism of BACE1 elevation is unclear. Furthermore, the normal function of BACE1 is poorly understood. We localized BACE1 in the brain at both the light and electron microscopic levels to gain insight into normal and pathophysiologic roles of BACE1 in health and AD, respectively. Our findings provide the first ultrastructural evidence that BACE1 localizes to vesicles (likely endosomes) in normal hippocampal mossy fiber terminals of both non-transgenic and APP transgenic (5XFAD) mouse brains. In some instances, BACE1-positive vesicles were located near active zones, implying a function for BACE1 at the synapse. In addition, BACE1 accumulated in swollen dystrophic autophagosome-poor presynaptic terminals surrounding amyloid plaques in 5XFAD cortex and hippocampus. Importantly, accumulations of BACE1 and APP co-localized in presynaptic dystrophies, implying increased BACE1 processing of APP in peri-plaque regions. In primary cortical neuron cultures, treatment with the lysosomal protease inhibitor leupeptin caused BACE1 levels to increase; however, exposure of neurons to the autophagy inducer trehalose did not reduce BACE1 levels. This suggests that BACE1 is degraded by lysosomes but not by autophagy. Our results imply that BACE1 elevation in AD could be linked to decreased lysosomal degradation of BACE1 within dystrophic presynaptic terminals. Elevated BACE1 and APP levels in plaque-associated presynaptic dystrophies could increase local peri-plaque Aβ generation and accelerate amyloid plaque growth in AD. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1152-3) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jul 2013 · Acta Neuropathologica
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    • "synaptic plasticity (Ashley et al., 2005; Sabo et al., 2003; Yamazaki et al., 1997). "
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    ABSTRACT: A role of amyloid β (Aβ) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated Aβ have been linked to synaptic and neuritic degeneration, consistent with the "dying-back" pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated Aβ remain elusive. In the last 2 decades, a variety of aggregated Aβ species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific Aβ assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated Aβ posit a mayor challenge for the identification of the most cardinal Aβ effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid β precursor protein (APP) as a molecular target for toxic Aβ assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking Aβ aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.
    Full-text · Article · May 2013 · Neurobiology of aging
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    • "In transfected human neuroblastoma cell line, α5β1 integrin appears to mediate the internalization and degradation of exogenous β-amyloid. When deposition of an insoluble amyloid around the α5β1-expressing cells is reduced, the cells show less apoptosis than the control cells (Matter et al., 1998; Yamazaki et al., 1997). Further studies on integrin such as α4β1 and α5β1 integrins in human brain tissue may provide more insight on the role of integrins in aging and Alzheimer's disease. "
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    ABSTRACT: This review focuses on the neurobiology of integrins, pathophysiological roles of integrins in neuroplasticity and nervous system disorders, and therapeutic implications of integrins as potential drug targets and possible delivery pathways. Neuroplasticity is a central phenomenon in many neurological conditions such as seizures, trauma, and traumatic brain injury. During the course of many brain diseases, in addition to intracellular compartment changes, alterations in non-cell compartments such as extracellular matrix (ECM) are recognized as an essential process in forming and reorganizing neural connections. Integrins are heterodimeric transmembrane receptors that mediate cell-ECM and cell-cell adhesion events. Although the mechanisms of neuroplasticity remain unclear, it has been suggested that integrins undergo plasticity including clustering through interactions with ECM proteins, modulating ion channels, intracellular Ca(2+) and protein kinase signaling, and reorganization of cytoskeletal filaments. As cell surface receptors, integrins are central to the pathophysiology of many brain diseases, such as epilepsy, and are potential targets for the development of new drugs for neurological disorders.
    Preview · Article · Apr 2012 · Pharmacology [?] Therapeutics
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