Current Drug Targets for Modulating Alzheimer's Amyloid Precursor Protein: Role of Specific Micro-RNA Species

Alzheimer’s disease (AD) is a common neurodegenerative disease whose prevalence increases with age. An increasing number of findings suggest that abnormalities in the metabolism of amyloid precursor protein (APP), a single transmembrane aspartic protein that is cleaved by β- and γ-secretases to produce β-amyloid protein (Aβ), are a major pathological feature of AD. In recent years, a large number of studies have been conducted on the APP processing pathways and the role of secretion. This paper provides a summary of the involvement of secretases in the processing of APP and the potential drug targets that could provide new directions for AD therapy.

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Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

Current Protein and Peptide Science ◽

10.2174/1389203721666200921152246 ◽

2020 ◽

Vol 21 (12) ◽

pp. 1164-1173

Author(s):

Siju Ellickal Narayanan ◽

Nikhila Sekhar ◽

Rajalakshmi Ganesan Rajamma ◽

Akash Marathakam ◽

Abdullah Al Mamun ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Early Onset ◽

Late Onset ◽

Precursor Protein ◽

Brain Disorder ◽

Amyloid Aβ ◽

T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

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The Role of Presenilin-1 in the γ-Secretase Cleavage of the Amyloid Precursor Protein of Alzheimer's Disease

Journal of Biological Chemistry ◽

10.1074/jbc.275.3.1525 ◽

2000 ◽

Vol 275 (3) ◽

pp. 1525-1528 ◽

Cited By ~ 32

Author(s):

Jean-Noël Octave ◽

Rachid Essalmani ◽

Bernadette Tasiaux ◽

Jean Menager ◽

Christian Czech ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Precursor Protein ◽

Presenilin 1

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What is the role of amyloid precursor protein dimerization?

Cell Adhesion & Migration ◽

10.4161/cam.4.2.11476 ◽

2010 ◽

Vol 4 (2) ◽

pp. 268-272 ◽

Cited By ~ 23

Author(s):

Naouel Ben Khalifa ◽

Joanne Van Hees ◽

Bernadette Tasiaux ◽

Sandra Huysseune ◽

Steven O. Smith ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Precursor Protein ◽

Protein Dimerization

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The Amyloid Precursor Protein Intracellular Domain-Fe65 Multiprotein Complexes: A Challenge to the Amyloid Hypothesis for Alzheimer's Disease?

International Journal of Alzheimer s Disease ◽

10.1155/2012/353145 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Daniel A. Bórquez ◽

Christian González-Billault

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Molecular Mechanisms ◽

Precursor Protein ◽

Amyloid Peptide ◽

Intracellular Domain ◽

Multiprotein Complexes ◽

Amyloid Cascade

Since its proposal in 1994, the amyloid cascade hypothesis has prevailed as the mainstream research subject on the molecular mechanisms leading to the Alzheimer's disease (AD). Most of the field had been historically based on the role of the different forms of aggregation ofβ-amyloid peptide (Aβ). However, a soluble intracellular fragment termed amyloid precursor protein (APP) intracellular domain (AICD) is produced in conjunction with Aβfragments. This peptide had been shown to be highly toxic in both culture neurons and transgenic mice models. With the advent of this new toxic fragment, the centerpiece for the ethiology of the disease may be changed. This paper discusses the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how this could be a potentially important new agent in the neurodegeneration observed in the AD.

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