Abstract
Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function that represents one of the most dramatic medical challenges for the aging population. Aβ peptides, generated by processing of the Amyloid Precursor Protein (APP), are thought to play a central role in the pathogenesis of AD. However, the network of physical and functional interactions that may affect their production and deposition is still poorly understood. The use of a bioinformatic approach based on human/mouse conserved coexpression allowed us to identify a group of genes that display an expression profile strongly correlated with APP. Among the most prominent candidates, we investigated whether the collagen chaperone HSP47 could be functionally correlated with APP. We found that HSP47 accumulates in amyloid deposits of two different mouse models and of some AD patients, is capable to physically interact with APP and can be relocalized by APP overexpression. Notably, we found that it is possible to reduce the levels of secreted Aβ peptides by reducing the expression of HSP47 or by interfering with its activity via chemical inhibitors. Our data unveil HSP47 as a new functional interactor of APP and imply it as a potential target for preventing the formation and/or growth amyloid plaques.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with a prevalence of approximately 2% in developed countries
Since the identification of our candidates was completely independent from a priori knowledge on amyloid precursor protein (APP) or AD, to validate our approach we evaluated how many candidates were already linked to APP and/or AD by experimental evidence
Most of the efforts that have been so far devoted to the identification of molecules that may affect AD pathogenesis by functionally interacting with APP were based on biochemical strategies or on genetic approaches [5]
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with a prevalence of approximately 2% in developed countries. The main constituents of SP are Ab-peptides, which are generated from b-amyloid precursor protein (APP) by sequential proteolytic cleavages, mediated by b- and c-secretases. APP is a ubiquitous type I transmembrane glycoprotein [4], alternative splicing can generate at least three main isoforms, characterized by important differences in their expression pattern. The short variant, known as APP695, is the most abundant isoform in mature brain, while longer isoforms, containing a Kunitz protease inhibitor (KPI) domain, such as the APP770, are the main variants expressed in the other tissues and during brain development [6,7]. KPI-positive APP isoforms could be important in brain under abnormal conditions, since their levels are significantly increased after traumatic injury [8], after seizures [9] and in AD patients [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
