engleski

The links between Alzheimer's disease and Niemann-Pick type C disease

Alzheimer’s disease (AD) and Niemann-Pick type C (NPC) disease are progressive neurodegenerative diseases with very different epidemiology and etiology. AD is a common cause of dementia with a complex polyfactorial etiology, including both genetic and environmental risk factors, while NPC is a very rare autosomal recessive disease. However, the diseases have important converging molecular pathways, including abnormal lipid metabolism, endolysosomal dysfunction and involvement of amyloid-β (Aβ) and tau pathology. Our recent studies have shown enhanced cleavage by beta-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1 disease mouse brains and in NPC1 mouse primary neurons. Indeed, we detected increased proteolysis of APP and also additional, recently identified BACE1 substrates, seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), which are primarily cleaved by BACE1. Furthermore, immunocytochemistry analysis revealed more punctuate staining of Sez6 and Sez6L in NPC1 vs. wt neurons, suggesting their accumulation within endosomal vesicles. We hypothesized that endosomal accumulation of BACE1-substrates in NPC1 cells is due to dysfunction of retromer transport. Subcellular and regional distribution of retromer proteins Vps26, Vps35 and receptor sorLA, and their levels were analyzed by immunocyto(histo)chemistry and Western blotting in: Chinese Hamster Ovary wild-type (CHOwt) and CHO NPC1-null cells ; hippocampi, cerebella and cortices of wt and NPC1 mice and in primary neurons from wt and NPC1 mice. Altered trafficking of retromer proteins was observed in NPC1-null vs. CHOwt cells. In NPC1 mouse brains we detected decreased SorLA immunostaining that was accompanied with Vps35 accumulation in the neuronal soma at early disease stage. In primary neurons retromer was sequestered in axons in NPC1 vs. wt neurons. Our studies indicate that altered BACE1-mediated proteolysis and retromer function are additional common features between AD and NPC. Thus, the reversal of BACE1 and/or retromer dysfunction may be considered as targets to ameliorate and/or develop treatments against still untreated and devastating neurodegenerative disorder NPC. Further studies of similarities and differences between AD and NPC will increase our understanding of both these devastating neurological diseases.

Alzheimer's disease ; APP ; BACE1 ; cholesterol ; neurodegeneration, NPC1, retromer

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