Amyloid-ß plaque formation and BACE1 accumulation in the brains of a 5xFAD Alzheimer's disease mouse model is associated with altered distribution and not proteolysis of BACE1 substrates Sez6 and Sez6L.
2022
Аутори:
Dominko, KristinaRastija, Ana
Smiljanić, Kosara
Mladenović, Aleksandra
Lešnjaković, Lucija
Kanazir, Selma
Milanović, Desanka
Hećimović, Silva
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2022 Elsevier B.V.
Метаподаци
Приказ свих података о документуАпстракт:
The formation of amyloid-ß peptides (Aß), that accumulate in Alzheimer's disease (AD) brains, involves proteolytic processing of the amyloid precursor protein (APP) firstly by ß-secretase (BACE1). Since BACE1 cleaves a plethora of other substrates, in this work we investigated whether the proteolysis and/or distribution of other BACE1 substrates, such as seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), is altered in AD. To test this we used 5xFAD mouse model brains that show an early accumulation of Aß plaques already at 2-months of age. Here we show for the first time that accumulation of BACE1 in peri-plaque regions and its enhanced levels in AD brains does not affect proteolysis of BACE1 substrates other than APP, such as Sez6 and Sez6L. We observed altered distribution of Sez6 and Sez6L in the area of Aß plaques in 5xFAD brains which is distinct to that of APP, BACE1 and/or LAMP1, suggesting different localization and/or function of these BACE1 substrates. While it is necessary to further elucidate the potential role that this may play in the course of AD, it is likely that Aß-targeted therapies may have beneficial effects against accumulation and/or altered distribution of BACE1 and its substrates, in addition to APP.
Кључне речи:
APP; Amyloid-ß; BACE1; Sez6; Sez6L; ß-secretaseИзвор:
Mechanisms of Ageing and Development, 2022, 207, 111726-Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
- Croatian Science Foundation IP-2016-06-2799
DOI: 10.1016/j.mad.2022.111726
ISSN: 0047-6374
PubMed: 35998821
WoS: 000851257600001
Scopus: 2-s2.0-85136612023
URI
https://linkinghub.elsevier.com/retrieve/pii/S0047637422001087http://radar.ibiss.bg.ac.rs/handle/123456789/5109