Naslov
Deciphering molecular links between Alzheimer’s disease and Niemann-Pick type C disease

Autori
Katušić Hećimović, Silva

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

Izvornik
Joint ICGEB – ALS Society of Canada Symposium on Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder : Abstract Book / - Department of Biotechnology, University of Rijeka, 2022, 25-25

Skup
Joint ICGEB – ALS Society of Canada Symposium on Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder

Mjesto i datum
Rijeka, Hrvatska, 30.06.2022. - 03.07.2022

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Alzheimer's disease ; neurodegeneration ; neuroinflammation ; Niemann-Pick type C disease ; NPC1

Sažetak
Niemann-Pick type C disease (NPC) is a rare inherited lysosomal storage disorder characterized by lysosomal cholesterol accumulation leading to progressive neurodegeneration and neuroinflammation. It is intriguing that this rare monogenic disease (caused by mutations in NPC1 or NPC2 genes) shows several key features of a complex Alzheimer's disease (AD). Using NPC disease cellular and animal models our goal is to elucidate both common and specific pathways involved in neurodegeneration and/or neuroinflammation in NPC and AD. We showed that proteolysis by the key AD protease BACE1 is enhanced in NPC1-null cells as well as in NPC1-null primary mouse neurons and NPC1-null mouse brains. Increased BACE1-mediated cleavage in NPC is mostly likely due to a defect within the endolysosomal transport resulting in accumulation of BACE1 and its substrates in endocytic compartments. Moreover, BACE1-inhibition and/or genetic depletion altered neurodegeneration of Purkinje neurons, lysosomal impairment and/or neuroinflammation (activation of astrocytes and microglia), suggesting that BACE1 and/or its substrates may play a role in the pathogenesis of NPC disease as well as in AD. Furthermore, we detected impaired retromer function in NPC. Changes in retromer distribution in NPC1 mouse brains were observed already at presymptomatic stage (at 4-weeks of age), indicating that retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverted retromer dysfunction, suggesting that retromer impairment in NPC is mechanistically dependent on cholesterol accumulation. Defects of the endolysosomal pathway are shared by other lysosomal storage disorders as well as the more common Alzheimer's and Parkinson's disease. Hence, the knowledge gained through our work could be used to better understand rare monogenic as well as more common and complex neurodegenerative disorders.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA