Genetic programming by the proteolytic fragments of the amyloid precursor protein: somewhere between confusion and clarity.
Mice engineered to overexpress disease-causing mutant amyloid precursor proteins (APP) display plaque deposition, but lack the hyperphosphorylated tau and massive neuronal loss characteristic of Alzheimer's disease (AD). Global gene expression profiles of brain regions from AD patients show upregulation of proapoptotic and inflammatory genes and down-regulation of neurotrophic, MAPK, phosphatase, and synaptic genes, while a profile of mice overexpressing a mutant APP shows the opposite trends in apoptotic and neurotrophic genes. The proteolytic fragments of the amyloid precursor protein have distinct biological actions. Both the gamma-secretase cleaved COOH-terminal fragment (CTFgamma) and the alpha-secretase cleaved NH2-terminal of APP (sAPPalpha) can regulate gene expression. While Abeta and CTFgamma can lead to toxicity and cell death, sAPPalpha promotes neurite outgrowth, enhances memory, and protects against a variety of insults, including Abeta toxicity. In AD, Abeta levels increase while sAPPalpha levels decrease. These subtleties in the levels of APP cleavage products are not reproduced in mice overexpressing mutant APP. In fact, the gene expression changes driven by sAPPalpha, such as increases in transthyretin and insulin-like growth factor 2, may protect these mice from high levels of Abeta.
Stein
Thor D
TD
Neuroscience Training Program, University of Wisconsin, Madison, WI 53705-2222, USA.
Johnson
Jeffrey A
JA
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013569:Synapses / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D020928:Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse