| First Author | Maulik M | Year | 2015 |
| Journal | Hum Mol Genet | Volume | 24 |
| Issue | 24 | Pages | 7132-50 |
| PubMed ID | 26433932 | Mgi Jnum | J:226837 |
| Mgi Id | MGI:5698744 | Doi | 10.1093/hmg/ddv413 |
| Citation | Maulik M, et al. (2015) APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer's disease. Hum Mol Genet 24(24):7132-50 |
| abstractText | Amyloid-beta (Abeta) peptides originating from beta-amyloid precursor protein (APP) are critical in Alzheimer's disease (AD). Cellular cholesterol levels/distribution can regulate production and clearance of Abeta peptides, albeit with contradictory outcomes. To better understand the relationship between cholesterol homeostasis and APP/Abeta metabolism, we have recently generated a bigenic ANPC mouse line overexpressing mutant human APP in the absence of Niemann-Pick type C-1 protein required for intracellular cholesterol transport. Using this unique bigenic ANPC mice and complementary stable N2a cells, we have examined the functional consequences of cellular cholesterol sequestration in the endosomal-lysosomal system, a major site of Abeta production, on APP/Abeta metabolism and its relation to neuronal viability. Levels of APP C-terminal fragments (alpha-CTF/beta-CTF) and Abeta peptides, but not APP mRNA/protein or soluble APPalpha/APPbeta, were increased in ANPC mouse brains and N2a-ANPC cells. These changes were accompanied by reduced clearance of peptides and an increased level/activity of gamma-secretase, suggesting that accumulation of APP-CTFs is due to decreased turnover, whereas increased Abeta levels may result from a combination of increased production and decreased turnover. APP-CTFs and Abeta peptides were localized primarily in early-/late-endosomes and to some extent in lysosomes/autophagosomes. Cholesterol sequestration impaired endocytic-autophagic-lysosomal, but not proteasomal, clearance of APP-CTFs/Abeta peptides. Moreover, markers of oxidative stress were increased in vulnerable brain regions of ANPC mice and enhanced beta-CTF/Abeta levels increased susceptibility of N2a-ANPC cells to H2O2-induced toxicity. Collectively, our results show that cellular cholesterol sequestration plays a key role in APP/Abeta metabolism and increasing neuronal vulnerability to oxidative stress in AD-related pathology. |
