Naslov
Enhanced proteolysis by the Alzheimer's protease BACE1 in NPC1 mouse brains is due to sequestration of its substrates within early endosomes

Autori
Rastija, Ana ; Meglaj, Sarah ; Tahirovic, Sabina ; Lichtenthaler, Stefan F. ; Hecimovic, Silva

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Skup
New Horizons in Alzheimer's Disease (Hybrid edition)

Mjesto i datum
Leuven, Belgija, 27.10.2021. - 28.10.2021

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
Niemann-Pick type C disease ; NPC1 ; Amyloid-beta peptides ; Aβ ; BACE1

Sažetak
Niemann-Pick type C (NPC) is a rare inherited lysosomal storage disorder that shares several pathological features with Alzheimer's disease (AD), including dysfunction of the endolysosomal pathway and increased levels of amyloid-beta peptides (Aβ). The Aβ peptides are generated by the proteolytic cleavage of the β-amyloid precursor protein (APP) initiated by the β-site amyloid precursor protein cleavage enzyme 1 (BACE1). We have previously shown in NPC1-null cells and in NPC1-mouse brains an enhanced cleavage by BACE1 of APP, and also exclusive BACE1 substrates, seizure protein 6 (Sez6), and seizure 6-like protein (Sez6L). In this work, we tested the hypothesis that enhanced proteolysis by BACE1 in NPC disease brains is due to accumulation of BACE1 and its substrates within the endolysosomal pathway. We performed endosome fractionation of 10-weeks old cerebella from wild type (wt) and NPC1 mice using ultracentrifugation in discontinuous sucrose gradient. Fractions were collected and analyzed by western blotting. The levels of free cholesterol were determined using the Amplex Red Cholesterol Assay kit. We observed increased levels and different distribution of late and early endocytic markers in NPC1 vs. wt fractions. Also, Sez6 and especially Sez6L showed different distribution in NPC1 vs. wt mouse cerebella. We noticed increased free cholesterol levels in late vs. early endosome fractions in NPC1 mouse cerebella. These findings support that altered endocytic trafficking of BACE1 and its substrates, and their accumulation within early endosomes may likely cause increased proteolysis by BACE1 in NPC disease brains. Further studies are needed to elucidate the potential role of BACE1 in the pathogenesis of NPC disease.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)

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