Targeting amyloid precursor protein shuttling and processing - long before amyloid beta formation (original) (raw)
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The Amyloid β-Protein Precursor and Alzheimers Disease. Therapeutic Approaches
Current Medicinal Chemistry-Central Nervous System Agents, 2005
Alzheimer's disease (AD) is triggered by the pathophysiological cleavage of a single transmembrane glycoprotein denominated amyloid β-protein precursor (AβPP) rendering amyloid β-peptide (Aβ) that aggregates in βsheets forming the neuritic plaques. Since AβPP is playing a key role in AD development, this review will be focused in the structure, proteolytic processing, related secretases, mutations, localization and physiological role of AβPP protein. AβPP is present in several tissues and can be spliced at different exons rendering up to ten AβPP isoforms. The most abundant isoforms are AβPP770, AβPP751 and AβPP695, being the last one the predominant isoform in neurons. Mutations in the AβPP sequence or in the secretases that cleavage AβPP determinate an early onset of AD. AβPP and the secretase activities involve in the non amyloidogenic and the amyloidogenic pathways are putative therapeutic targets in AD, but their relationships with other physiological functions can produce controversial results.
Pharmacology & Therapeutics, 2000
The amyloid  precursor protein (A  PP), which plays a pivotal role in Alzheimer's disease (AD), can exist as either a membranebound or soluble protein. The former is cleaved at the level of the plasma membrane to generate the soluble form of the protein (A  PP s). An alternative pathway exists, however, for the cleavage of A  PP to generate a 40-42 amino acid peptide termed amyloid  (A ), either within the lysosomal or the endoplasmic reticulum/Golgi compartments of the cell. In AD, there is an increase in the ratio of the 42 amino acid form of the A  peptide (A  42) to A  40. The A  42 form is the more amyloidogenic form and has an increased potential to form the insoluble amyloid deposits characteristic of AD pathology. Studies on the familial form of the disease, with mutations in A  PP or in the presenilin proteins, have confirmed an increase in A  42 generation associated with the early stages of the disease. This review will examine the factors that influence A  PP processing, how they may act to modulate the biological effects of A  PP s and A  , and if they provide a viable target for therapeutic intervention to modify the rate of progression of the disease.
Pharmacological targeting of the β-amyloid precursor protein intracellular domain
Scientific Reports, 2014
Amyloid precursor protein (APP) intracellular domain (AICD) is a product of APP processing with transcriptional modulation activity, whose overexpression causes various Alzheimer's disease (AD)-related dysfunctions. Here we report that 1-(39,49-dichloro-2-fluoro[1,19-biphenyl]-4-yl)-cyclopropanecarboxylic acid) (CHF5074), a compound that favorably affects neurodegeneration, neuroinflammation and memory deficit in transgenic mouse models of AD, interacts with the AICD and impairs its nuclear activity. In neuroglioma-APPswe cells, CHF5074 shifted APP cleavage from Ab 42 to the less toxic Ab 38 peptide without affecting APP-C-terminal fragment, nor APP levels. As revealed by photoaffinity labeling, CHF5074 does not interact with c-secretase, but binds to the AICD and lowers its nuclear translocation. In vivo treatment with CHF5074 reduced AICD occupancy as well as histone H3 acetylation levels and transcriptional output of the AICD-target gene KAI1. The data provide new mechanistic insights on this compound, which is under clinical investigation for AD treatment/prevention, as well as on the contribution of the AICD to AD pathology.
Signaling effect of amyloid-β42 on the processing of AβPP
Experimental Neurology, 2010
The effects of amyloid-β are extremely complex. Current work in the field of Alzheimer disease is focusing on discerning the impact between the physiological signaling effects of soluble low molecular weight amyloid-β species, and the more global cellular damage that could derive from highly concentrated and/or aggregated amyloid. Being able to dissect the specific signaling events, to understand how soluble amyloid-β induces its own production by upregulating BACE1 expression, could lead to new tools to interrupt the distinctive feedback cycle with potential therapeutic consequences. Here we describe a positive loop that exists between the secretases that are responsible for the generation of the amyloid-β component of Alzheimer disease. According to our hypothesis, in familial Alzheimer disease, the primary overproduction of amyloid-β can induce BACE1 transcription and drive a further increase of amyloid-β precursor protein processing and resultant amyloid-β production. In sporadic Alzheimer disease, many factors, among them oxidative stress and inflammation, with consequent induction of presenilins and BACE1, would activate a loop and proceed with the generation of amyloid-β and its signaling role onto BACE1 transcription. This concept of a signaling effect by and feedback on the amyloid-β precursor protein will likely shed light on how amyloid-β generation, oxidative stress, and secretase functions are intimately related in sporadic Alzheimer disease.
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.
Amyloid beta-protein assembly as a therapeutic target of Alzheimer's disease
Current pharmaceutical design, 2008
Alzheimer's disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the amyloid beta-protein (Abeta), a 40-42 amino acid peptide. The folding of Abeta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. Abeta is formed through cleavage of the Abeta precursor protein by two endoproteinases, beta-secretase and gamma-secretase, that cleave the Abeta N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting Abeta production, assembly, clearance, and neurotoxicity. Currently, no disease-modifying therapeutic agents are available for AD patients. Instead, existing therapeutics provide only modest symptomatic benefits for a limited time. We summarize here recent efforts to produce therapeutic drugs targeting Abeta assembly. A number of approaches are being used in these efforts, includi...
Current Medicinal Chemistry, 2006
There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid β (Aβ) in the pathogenic cascade of Alzheimer's disease (AD). Different Aβ assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for AD suggest that intraneuronal accumulation of Aβ oligomers might be involved in AD pathogenesis at a very early stage of the disease. The detrimental effect of oligomeric Aβ on synaptic efficacy is suggested to be an early event in the pathogenic cascade. Also early neuronal responses as activation of the unfolded protein response are processes likely to be associated with the increased occurrence of oligomeric or low fibrillar Aβ in AD pathology. In later stages of AD pathology, the fibrillarity of Aβ increases, concomitantly with a neuroinflammatory response, followed by tau related neurofibrillary changes in end stage pathology. We will review recent findings in in vitro cell models, in vivo mouse models, and post mortem AD brain tissue in view of the effects of different Aβ peptide species on neurodegeneration during AD pathogenesis. Insight into the role of different Aβ species during AD pathogenesis is essential for the development of disease modifying drugs and therapeutical strategies.