Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2

Yang, Guang; Gong, Yan Dao; Gong, Kai; Jiang, Wu Ling; Kwon, Elaine; Wang, Pei; Zheng, Hui; Zhang, Xiu Fang; Gan, Wen Biao; Zhao, Nan

doi:10.1016/j.neulet.2005.04.040

Cited by 90 publications

(61 citation statements)

References 33 publications

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“…Our data suggest that the APP family dependent regulation of SAM might be responsible for the proper generation of acetylcholine. This hypothesis fits to reports of disturbed synaptic vesicle density and synaptic failure in APP/APLP2 knockout mice (9,52) as well as to cranial abnormalities (7) putatively resulting from cholinergic neuron dysfunction. Cholinergic decline is central hallmark of AD manifesting the cholinergic hypothesis.…”

Section: ϫ3supporting

confidence: 90%

The Amyloid Precursor Protein (APP) Family Members are Key Players in S-adenosylmethionine Formation by MAT2A and Modify BACE1 and PSEN1 Gene Expression-Relevance for Alzheimer's Disease

Schrötter

Pfeiffer

Magraoui

et al. 2012

Molecular & Cellular Proteomics

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The amyloid precursor protein (APP)1 is a species-conserved integral membrane protein, which is expressed in many tissues. A role for APP has been suggested in neurite outgrowth and synaptogenesis, protein trafficking along axons, cell adhesion, calcium metabolism, and signal transduction (reviewed in (1, 2)). During its life cycle, APP is cleaved into various fragments mediating different functions. Next to A␤ (and the p3 fragment), extracellular soluble fragments (sAPP␣ or sAPP␤), and intracellular fragments (APP intracellular domain, AICD) are generated. After sequential ␤-and

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Section: ϫ3supporting

confidence: 90%

The Amyloid Precursor Protein (APP) Family Members are Key Players in S-adenosylmethionine Formation by MAT2A and Modify BACE1 and PSEN1 Gene Expression-Relevance for Alzheimer's Disease

Schrötter

Pfeiffer

Magraoui

et al. 2012

Molecular & Cellular Proteomics

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“…These findings are correlated with several works that shows that the dynamics of APP processing has a clear effect on synaptic function [25,29].…”

Section: Cfm)supporting

confidence: 89%

Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

et al. 2006

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Alzheimer's disease (AD) is one of the main causes of dementia in the world. Increases in life expectancy in the majority of populations around the world have been associated with a higher rate of AD incidence in different countries in past and future decades [1] AD is clinically characterized by cognitive impairment; there is an initial alteration in recent AbstractIn this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.

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“…Analysis of single and double knock-out (KO and dKO) mice has shown that App-KO, Aplp1-KO, Aplp2-KO, and App/ Aplp1-dKO have minor deficits. In contrast, App/Aplp2-dKO mice have severe neuromuscular junctions deficits, are significantly smaller than App-KO and Aplp2-KO mice, and die within the first 28 days of life (25,43,102,103). These data indicate that APP and APLP2 share some essential function that cannot be compensated for by APLP1.…”

Section: Tablementioning

confidence: 90%

Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

Rice

Rajadhyaksha

et al. 2016

Journal of Biological Chemistry

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The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH 2 terminus of the ACR, and CRL4 CRBN , which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn. APP shares essential functions with APP-like protein-2 (APLP2) but not APP-like protein-1 (APLP1 The ACR facilitated in vitro ubiquitination of presynaptic proteins that regulate exocytosis, suggesting a mechanism by which APP tunes transmitter release. Other dementia-related proteins, namely Tau and apoE, interact with and are ubiquitinated via the ACR in vitro. This, and the evidence that CRBN and CUL4B are linked to intellectual disability, prompts us to hypothesize a pathogenic mechanism, in which APP acts as a modulator of E3 ubiquitin-protein ligase(s), shared by distinct neuronal disorders. The well described accumulation of ubiquitinated protein inclusions in neurodegenerative diseases and the link between the ubiquitin-proteasome system and neurodegeneration make this concept plausible. Processing of APP2 plays an important role in the central nervous system. A polymorphism in APP that reduces APP processing protects from sporadic Alzheimer disease (AD) (1). In contrast, mutations in APP and in genes that regulate APP processing, such as PSENs and BRI2/ITM2B, cause familial dementias (2-12). APP is cleaved by ␤-secretase/BACE1 into a soluble ectodomain (soluble APP␤) and the COOH-terminal fragment ␤-CTF. Alternatively, ␣-secretase cleaves APP into soluble APP␣ and a shorter COOH-terminal fragment, ␣-CTF. ␤-CTF and ␣-CTF can be cleaved by ␥-secretase to produce A␤ and the APP intracellular domain (AID) or P3 and AID, respectively (13-17). AID contains the ACR plus a few amino acids derived from the trans-membrane region of APP. AID is released in the cytosol upon production. Another processing pathway involves cleavage of APP in the ACR by caspase-6, -3, and -8 (18 -24). Sequential ␥-secretase/caspase processing can potentially generate the NH 2 -and COOH-terminal cytosolic peptides JCasp and Ccas (23,24).In vivo studies have identified an essential role for the ACR in the patterning of neuromuscular junction and survival and in synaptic transmission (25)(26)(27)(28)(29). Other studies have suggested that release of AID modulates apoptosis, gene transcription, and Ca 2ϩ homeostasis (23, 30 -40). The caspase-derived APP fragments Ccas and JCasp also possess toxic activities (22)(23)(24). Overall, these data indicate that the ACR is functionally important in vivo.APP belongs to a protein family that includes APLP1 and APLP2. APLP1 and APLP2 are processed like APP (41-45) and release intracellular peptides, called ALID1 and ALID2, respectiv...

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Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2

Cited by 90 publications

References 33 publications

The Amyloid Precursor Protein (APP) Family Members are Key Players in S-adenosylmethionine Formation by MAT2A and Modify BACE1 and PSEN1 Gene Expression-Relevance for Alzheimer's Disease

The Amyloid Precursor Protein (APP) Family Members are Key Players in S-adenosylmethionine Formation by MAT2A and Modify BACE1 and PSEN1 Gene Expression-Relevance for Alzheimer's Disease

Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

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