Alzheimer's disease (AD) research has shown that patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (the primary component of the amyloid deposits found in AD brains). However, it is not clear how the presenilins contribute to this increase. New findings now show that the presenilins affect APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is known that the presenilins are involved in the cleavage of the Notch receptor, hinting that they either directly regulate gamma-secretase activity or themselves are protease enzymes. These findings suggest that the presenilins may prove to be valuable molecular targets for the development of drugs to combat AD.
"In addition, APP, its processing machinery , and the AICD impact signalling independent of Aí µí»½ formation (reviewed in ). For instance, PS1, a subunit of the í µí»¾-secretase complex, cleaves numerous transmembrane signalling receptors and transducers other than APP CTFs, including Notch, cadherins, ErbB4, LDL receptor related proteins, and so forth  . In addition, PS1 and PS2 impact signalling pathways directly. "
[Show abstract][Hide abstract] ABSTRACT: Although a wide variety of genetic and nongenetic Alzheimer's disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively.
BioMed Research International 08/2014; 2014:167024. DOI:10.1155/2014/167024 · 2.71 Impact Factor
"BACE1-digested APP CTFs are subsequently cleaved by the γ-secretase complex to release Aβ. In addition, γ-secretase cleaves a series of functionally important substrates such as NOTCH  and tyrosinase . γ-secretase activity is produced from a high molecular weight complex consisting of at least four transmembrane components: presenilin (PS, with two mammalian homologs as PS1 and PS2), nicastrin, anterior pharynx-defective-1 (APH-1), and presenilin enhancer-2 (PEN2) [140,141]. "
[Show abstract][Hide abstract] ABSTRACT: The beta-amyloid (Abeta) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer's disease (AD). Abeta is produced through sequential cleavage of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Abeta generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.
"Alzheimer's disease (AD) is a neurodegenerative disorder with progression of cognitive decline (Forman et al. 2004). AD is histopathologically characterised by the presence of extracellular amyloid-beta (Ab) peptide plaques and intracellular neurofibrilliary tangle in brain (Haass & De Strooper 1999). Extensive studies have indicated that Ab aggregates are the neurotoxic species in AD (Liu et al. 2006). "
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