Proteolytic processing of Alzheimer’s β-amyloid precursor protein

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, College of Medicine, Xiamen University, Xiamen, Fujian, China.
Journal of Neurochemistry (Impact Factor: 4.28). 11/2011; 120 Suppl 1(Suppl. 1):9-21. DOI: 10.1111/j.1471-4159.2011.07519.x
Source: PubMed


J. Neurochem. (2012) 120 (Suppl. 1), 9–21.
β-Amyloid precursor protein (APP) is a critical factor in the pathogenesis of Alzheimer’s disease (AD). APP undergoes post-translational proteolysis/processing to generate the hydrophobic β-amyloid (Aβ) peptides. Deposition of Aβ in the brain, forming oligomeric Aβ and plaques, is identified as one of the key pathological hallmarks of AD. The processing of APP to generate Aβ is executed by β- and γ-secretase and is highly regulated. Aβ toxicity can lead to synaptic dysfunction, neuronal cell death, impaired learning/memory and abnormal behaviors in AD models in vitro and in vivo. Aside from Aβ, proteolytic cleavages of APP can also give rise to the APP intracellular domain, reportedly involved in multiple types of cellular events such as gene transcription and apoptotic cell death. In addition to amyloidogenic processing, APP can also be cleaved by α-secretase to form a soluble or secreted APP ectodomain (sAPP-α) that has been shown to be mostly neuro-protective. In this review, we describe the mechanisms involved in APP metabolism and the likely functions of its various proteolytic products to give a better understanding of the patho/physiological functions of APP.

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    • "In contrast, in the amyloidogenic pathway, APP is cleaved by β-secretase, generating a membrane-associated fragment (Zhang et al., 2012). Subsequently, γ-secretase releases Aβ, which tends to aggregate, giving rise to senile plaques and other insoluble oligomeric forms of the protein. "
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    ABSTRACT: Alzheimer disease (AD) is the most common form of age-related dementia. The etiology of AD is considered to be multifactorial as only a negligible percentage of cases have a familial or genetic origin. Glycogen synthase kinase-3 (GSK-3) is regarded as a critical molecular link between the two histopathological hallmarks of the disease, namely senile plaques and neurofibrillary tangles. In this review, we summarize current data regarding the involvement of this kinase in several aspects of AD development and progression, as well as key observations highlighting GSK-3 as one of the most relevant targets for AD treatment.
    Full-text · Article · May 2014 · Frontiers in Molecular Neuroscience
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    • "One of the major conclusions of this study was that A␤PP displays a heterogeneous distribution among different types of synapses in the hippocampus: thus less than half of the hippocampal synapses were endowed with A␤PP and this protein was most abundantly localized in glutamatergic rather than in GABAergic or cholinergic synapses. This is of particular interest when considering that A␤PP distribution should define the generation of A␤ peptides [8] [9], which is considered the major candidate culprit in AD [10] [11]. In fact, the loss of synaptic markers (e.g., [15] [56]) and the loss of synapses (e.g., [12] [14]) are some of the earliest changes associated with mild cognitive impairment and early AD. "
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    ABSTRACT: Amyloid-β protein precursor (AβPP) is a large transmembrane protein highly expressed in the central nervous system and cleavage of it can produce amyloid-β peptides (Aβ) involved in synaptic dysfunction and loss associated with cognitive impairment in Alzheimer's disease (AD). Surprisingly, little is known about the synaptic and sub-synaptic distribution of AβPP in different types of nerve terminals. We used total, synaptic, sub-synaptic, and astrocytic membrane preparations obtained from the hippocampus of adult rats to define the localization of AβPP, using two different antibodies against different AβPP epitopes. Western blot analysis revealed that AβPP was not significantly enriched in synaptosomal as compared to total membranes. Within synapses, AβPP immunoreactivity was more abundant in pre- (60 ± 4%) than post- (30 ± 5%) or extra-synaptic fractions (10 ± 2%). Immunocytochemical analysis of purified nerve terminals indicated that AβPP was more frequently associated with glutamatergic (present in 31 ± 4% of glutamatergic terminals) rather than with GABAergic (16 ± 3%) or cholinergic terminals (4 ± 1%, n = 4). We also observed a general lack of co-localization of AβPP and GFAP immunoreactivities in the hippocampus of sections of adult rat brain, albeit we could detect the presence of AβPP in gliosomes (vesicular specializations of astrocytic membranes), suggesting that AβPP has a heterogeneous localization restricted to certain regions of astrocytes. These results provide the first direct demonstration that AβPP is mostly distributed among glutamatergic rather than GABAergic or cholinergic terminals of the adult rat hippocampus, in remarkable agreement with the particular susceptibility to dysfunction and degeneration of glutamatergic synapses in early AD.
    Full-text · Article · Feb 2014 · Journal of Alzheimer's disease: JAD
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    • "In the amyloidogenic pathway, APP is cleaved initially by the β-site APP-cleaving enzyme (BACE), releasing a soluble APP fragment (sAPPβ) that is secreted outside the cell, leaving behind a membrane-associated C-terminal fragment of 99 or 89 amino acids [C99 or C89 (CTFβ)]. The CTFβ is then cleaved by γ-secretase, generating the Aβ peptide and a cytoplasmic APP intracellular domain (AICD) (Chow et al., 2010; Zhang et al., 2012). Aβ 42 peptide oligomerizes, is neurotoxic (Iijima et al., 2004), and readily forms aggregates that accumulate in the brain to form plaques (Small et al., 2001). "
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    ABSTRACT: Alzheimer's Disease (AD) is an age related neurodegenerative disease characterized by memory loss and decreased synaptic function. Advances in transgenic animal models of AD have facilitated our understanding of this disorder, and have aided in the development, speed, and efficiency of testing potential therapeutics. Recently, we have described the characterization of a novel model of AD in the fruit fly, Drosophila melanogaster, where we expressed the human AD associated proteins APP and BACE in the central nervous system of the fly. Here we describe synaptic defects in the larval neuromuscular junction (NMJ) in this model. Our results indicate that expression of human APP and BACE at the larval NMJ lead to defective larval locomotion behavior, decreased pre-synaptic connections, altered mitochondrial localization in presynaptic motor neurons, and decreased postsynaptic protein levels. Treating larvae expressing APP and BACE with the γ-secretase inhibitor L-685, 458 suppresses the behavioral defects as well as the pre- and postsynaptic defects. We suggest that this model will be useful to assess and model the synaptic dysfunction normally associated with AD, and will also serve as a powerful in vivo tool for rapid testing of potential therapeutics for AD.
    Full-text · Article · Jan 2014 · Disease Models and Mechanisms
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