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?-Amyloid precursor protein (APP) and the human diseases.

ABSTRACT: Several pathophysiological functions of the human ?-amyloid precursor protein (APP) have been recently proposed in different human diseases such as neurodevelopmental and neurodegenerative disorders including rare diseases such as autism, fragile X syndrome, amyotrophic lateral sclerosis, multiple sclerosis, Lesch-Nyhan disease; common and complex disorders such as Alzheimer's disease; metabolic disorders such as diabetes; and also cancer. APP as well as all of its proteolytic fragments including the amyloid-? (A?) peptide, are part of normal physiology. The targeting of the components of APP proteolytic processing as a pharmacologic strategy will not be without consequences. Recent research results highlight the impact of alternative splicing (AS) process on human disease, and may provide new directions for the research on the impact of the human APP on human diseases. The identification of molecules capable of correcting and/or inhibiting pathological splicing events is therefore an important issue for future therapeutic approaches. To this end, the defective APP-mRNA isoform responsible for the disease in cells and tissues appears as an ideal target for epigenetic therapeutic intervention and antisense drugs are potential treatment.

SUBMITTER: Nguyen KV

PROVIDER: S-EPMC7179352 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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β-Amyloid precursor protein (APP) and the human diseases.

Nguyen Khue Vu KV

AIMS neuroscience 20191029 4

Several pathophysiological functions of the human β-amyloid precursor protein (APP) have been recently proposed in different human diseases such as neurodevelopmental and neurodegenerative disorders including rare diseases such as autism, fragile X syndrome, amyotrophic lateral sclerosis, multiple sclerosis, Lesch-Nyhan disease; common and complex disorders such as Alzheimer's disease; metabolic disorders such as diabetes; and also cancer. APP as well as all of its proteolytic fragments includin ...[more]

PMID: 32341983

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Project description:The Î²-amyloid precursor protein APP and the related APLPs, undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that AÎ² accumulation is a central trigger for Alzheimer disease (AD), the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsÎ± ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The Î³-secretase generated APP intracellular domain AICD, functions as a transciptional regulator in heterologous reporter assays, although its role for endogenous gene regulation has remained controversial. To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators we performed a DNA microarray transcriptome profiling of the frontal cortex of adult wild type, APP-/-, APLP2-/- and APPsÎ± knockin (KI) mice, APPÎ±/Î±, expressing solely the secreted APPsÎ± ectodomain. Biological pathways affected by the lack of APP family members included regulation of neurogenesis, regulation of transcription and regulation of neuron projection development. Comparative analysis of transcriptome changes and qPCR validation identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity related genes that were down-regulated in knock-out cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including Bace1, Kai1, Gsk3b, p53, Tip60 and Vglut2. Only Egfr was slightly up-regulated in APLP2-/- mice. Comparison of APP-/- and APPÎ±/Î± with wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2-/- on different genetic backgrounds revealed that background related transcriptome changes may dominate over changes due to the knockout of a single gene. Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells. Prefrontal cortices of adult male mice (24 - 28 weeks) of the following genotypes were analyzed: WT (n=3), APP-/- (n=3), APPÎ±/Î± (n=3), APLP2-/- (n=3), APLP2(R1)-/- (n=3). WT, APP-/-, APPÎ±/Î±, APLP2-/- had been backcrossed for six generations to C57BL/6 mice. APLP2(R1)-/- harbors the identical knockout allele as APLP2-/- but was back-crossed only once.

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?-Amyloid precursor protein (APP) and the human diseases.

Publications

β-Amyloid precursor protein (APP) and the human diseases.

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