Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging (original) (raw)
Related papers
Progress in Neurobiology, 2007
The amyloid precursor protein (APP) is a transmembrane protein that plays major roles in the regulation of several important cellular functions, especially in the nervous system, where it is involved in synaptogenesis and synaptic plasticity. The secreted extracellular domain of APP, sAPPa, acts as a growth factor for many types of cells and promotes neuritogenesis in post-mitotic neurons. Alternative proteolytic processing of APP releases potentially neurotoxic species, including the amyloid-b (Ab) peptide that is centrally implicated in the pathogenesis of Alzheimer's disease (AD). Reinforcing this biochemical link to neuronal dysfunction and neurodegeneration, APP is also genetically linked to AD. In this review, we discuss the biological functions of APP in the context of tissue morphogenesis and restructuring, where APP appears to play significant roles both as a contact receptor and as a diffusible factor. Structural investigation of APP, which is necessary for a deeper understanding of its roles at a molecular level, has also been advancing rapidly. We summarize recent progress in the determination of the structure of isolated APP fragments and of the conformations of full-length sAPPa, in both monomeric and dimeric states. The potential role of APP dimerization for the regulation of its biological functions is also discussed. #
Cellular and Molecular Life Sciences, 2020
Amyloid precursor protein (APP) is a transmembrane protein expressed largely within the central nervous system. Upon cleavage, it does not produce the toxic amyloid peptide (Aβ) only, which is involved in neurodegenerative progressions but via a non-amyloidogenic pathway it is metabolized to produce a soluble fragment (sAPPα) through α-secretase. While a lot of studies are focusing on the role played by APP in the pathogenesis of Alzheimer's disease, sAPPα is reported to have numerous neuroprotective effects and it is being suggested as a candidate with possible therapeutic potential against Alzheimer's disease. However, the mechanisms through which sAPPα precisely works remain elusive. We have presented a comprehensive review of how sAPPα is regulating the neuroprotective effects in different biological models. Moreover, we have focused on the role of sAPPα during different developmental stages of the brain, neurogenic microenvironment in the brain and how this metabolite of APP is regulating the neurogenesis which is regarded as a compelling approach to ameliorate the impaired learning and memory deficits in dementia and diseases like Alzheimer's disease. sAPPα exerts beneficial physiological, biochemical and behavioral effects mitigating the detrimental effects of neurotoxic compounds. It has shown to increase the proliferation rate of numerous cell types and promised the synaptogenesis, neurite outgrowth, cell survival and cell adhesion. Taken together, we believe that further studies are warranted to investigate the exact mechanism of action so that sAPPα could be developed as a novel therapeutic target against neuronal deficits.
Scientific Reports, 2016
Amyloid precursor protein (APP) and its cleavage product amyloid β (Aβ) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. α-Cleaved soluble APP (sAPPα) was secreted early during differentiation, from neuronal progenitors, while β-cleaved soluble APP (sAPPβ) was first secreted after deep-layer neurons had formed. Short Aβ peptides, including Aβ1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as Aβ1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by Aβ1-40/42, is associated with mature neuronal phenotypes. Amyloid precursor protein (APP) is a type I transmembrane protein essential for normal brain development and possibly also for adult brain plasticity 1. APP and its cleavage product amyloid β (Aβ) have been studied extensively in relation to Alzheimer's disease (AD) 2. The Aβ cascade hypothesis, first postulated in 1991 3 , posits that an imbalance in the production and clearance of the aggregation-prone 42 amino acid-long form of Aβ (Aβ1-42) results in deposition of the peptide in senile plaques in the brain parenchyma, which initiates a neurotoxic cascade that ultimately leads to AD dementia 2. APP can undergo at least two major proteolytic processing pathways as shown in Fig. 1: (A) the nonamyloidogenic, α-secretase-dependent pathway, in which α-secretase cleaves in the middle of the Aβ sequence precluding formation of full length Aβ. This activity generates a soluble APP fragment (sAPPα) and a membrane-bound
The effect of stress on the expression of the amyloid precursor protein in rat brain
Neuroscience Letters, 2008
The abnormal processing of the amyloid precursor protein (APP) is a pivotal event in the development of the unique pathology that defines Alzheimer's disease (AD). Stress, and the associated increase in corticosteroids, appear to accelerate brain ageing and may increase vulnerability to Alzheimer's disease via altered APP processing. In this study, rats were repeatedly exposed to an unavoidable stressor, an open elevated platform. Previous studies in this laboratory have shown that a single exposure produces a marked increase in plasma corticosterone levels but animals develop tolerance to this effect between 10 and 20 daily sessions. Twenty-four hours after stress, there was an increase in the ratio of the deglycosylated form of APP in the particulate fraction of the brain, which subsequently habituated after 20 days. The levels of soluble APP (APPs) tended to be lower in the stress groups compared to controls except for a significant increase in the hippocampus after 20 days of platform exposure. Since APPs is reported to have neurotrophic properties, this increased release may represent a neuroprotective response to repeated stress. It is possible that the ability to mount this response decreases with age thus increasing the vulnerability to stress-induced AD-related pathology.
The roles of amyloid precursor protein (APP) in neurogenesis
Cell Adhesion & Migration, 2011
Neurodegenerative diseases such as Alzheimer disease (AD) are characterized by the progressive loss of neurons which are regionspecific in the brain. Accumulative evidences support the amyloid hypothesis for AD pathogenesis that amyloid-beta (Aβ), derived from amyloid precursor protein (APP), plays a crucial initial role that triggers a complex pathological cascade which leads to the neurodegenerative conditions observed in the disorder. 1 Recently,
Biochemical and …, 1992
The recent discovery that point mutations in the #/A4 amyloid precursor protein may be the cause of certain forms of familial Alzheimer s disease provides strong support for the view that a thorough understanding of the metabolism of this protein may elucidate the pathogenesis of most forms of the disease and thus serve as a basis for rational prevention and therapy. Here we show that overexpression of a portion of the amyloid precursor protein molecule produces at least four distinct fragments of the COOH-terminus of amyloid precursor protein, suggesting altered proteolysis of amyloid precursor protein, and that such overexpression is associated with cytotoxicity. The degree of toxicity in the P19 cell culture model (differentiating mouse embryonal carcinoma cells) is shown to be related to the two larger novel COOH-terminal protein fragments (16 an(14 kilodalton), as well as to levels of expression of these two tragments. The toxicity is manifested in several differentiated cell hneages, including neuronal cells. ~ ~992 Ao~demio Press, Inc. The #/A4 amyloid polypeptide accumulates in the aging brains of a variety of mammalian species with contrasting maximum lifespan potentials (1). Thus, the rates of its deposition appear to be coupled to intrinsic biological aging rather than merely to chronological time. Large quantities of this material are found within the cerebral blood vessels and neuritic plaques of patients with dementia of the Alzheimer's type, a disorder which exhibits an exponential increase in age-specific incidence in human subjects beginning at about age 60. Subjects born with an extra copy of chromosome 21, which harbors the structural gene for the O/A4 amyloid precursor protein (APP), develop this pathology prematurely, as do certain individuals who carry point mutations in the APP gene (2-4). Mutation at the affected codon is thought to impair translational regulation of the synthesis of APP, possibly resulting in overexpression of the protein (5).
One of the major neuropathological hallmarks of Alzheimer's disease is the presence of senile plaques in vulnerable regions of CNS. These plaques are formed of aggregated amyloid peptide. Amyloid peptide is released by the cleavage of its precursor (APP). The establishment of cell lines expressing human APP allowed to characterize both amyloidogenic and non-amyloidogneic pathways of APP catabolism and to identify some of the proteins involved in this processing (known as secretases). This led to a better comprehension of amyloid peptide production, which needs to be further characterized since g-secretase is as yet not identi®ed; moreover, we still lack a clear overview of the interactions between APP and other proteins promoting Alzheimer's disease (tau, presinilins¼). An important limitation of these cell lines for studying the mechanisms involved in Alzheimer's disease is supported by the observation that human APP expression does not modify transfected cells survival. The infection of primary neuronal cultures with full-length human APP indicates that APP expression induces neuronal apoptosis by itself; this neurotoxicity does not rely on extracellular production of APP derivatives (secreted APP, amyloid peptide). It is now essential to understand, in neuronal models, the production, localization and involvement of amyloid peptide in neurodegenerative processes. q
The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes
Acta Neuropathologica, 2014
The amyloid precursor protein (APP) has occupied a central position in Alzheimer's disease (AD) pathophysiology, in large part due to the seminal role of amyloid-β peptide (Aβ), a proteolytic fragment derived from APP. Although the contribution of Aβ to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP's involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some even harbor neuroprotective effects. In this review, we will explore this complex picture by first discussing the pleiotropic effects of the major APP-derived peptides cleaved by multiple proteases, including soluble APP peptides (sAPPα, sAPPβ), various C-and Nterminal fragments, p3, and APP intracellular domain fragments. In addition, we will highlight two interesting sequences within APP that likely contribute to this duality in APP function. First, it has been found that caspase-mediated cleavage of APP in the cytosolic region may release a cytotoxic peptide, C31, which plays a role in synapse loss and neuronal death. Second, recent studies have implicated the-YENPTY-motif in the cytoplasmic region as a domain that modulates several APP activities through phosphorylation and dephosphorylation of the first tyrosine residue. Thus, this review summarizes the current understanding of various APP proteolytic products and the interplay among them to gain deeper insights into the possible mechanisms underlying neurodegeneration and AD pathophysiology.