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- Dentoni, Giacomo, et al.
(författare)
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Mitochondrial Alterations in Neurons Derived from the Murine AppNL-F Knock-In Model of Alzheimer's Disease
- 2022
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:2, s. 565-583
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Tidskriftsartikel (refereegranskat)abstract
- Background:Alzheimer’s disease (AD) research has relied on mouse models overexpressing human mutant A βPP; however, newer generation knock-in models allow for physiological expression of amyloid-β protein precursor (AβPP) containing familial AD mutations where murine AβPP is edited with a humanized amyloid-β (Aβ) sequence. The AppNL-F mouse model has shown substantial similarities to AD brains developing late onset cognitive impairment.Objective:In this study, we aimed to characterize mature primary cortical neurons derived from homozygous AppNL-F embryos, especially to identify early mitochondrial alterations in this model.Methods:Primary cultures of AppNL-F neurons kept in culture for 12–15 days were used to measure Aβ levels, secretase activity, mitochondrial functions, mitochondrial-ER contacts, synaptic function, and cell death.Results:We detected higher levels of Aβ42 released from AppNL-F neurons as compared to wild-type neurons. AppNL-F neurons, also displayed an increased Aβ42/Aβ40 ratio, similar to adult AppNL-F mouse brain. Interestingly, we found an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL-F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which may account for upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function.Conclusion:We show that widespread mitochondrial alterations can be detected in AppNL-F neurons in vitro, where amyloid plaque deposition does not occur, suggesting soluble and oligomeric Aβ-species being responsible for these alterations.
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| 2. |
- Santos Leal, Nuno João
(författare)
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The interplay between mitochondria-endoplasmic reticulum contacts and Alzheimer’s disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Even though Alzheimer’s disease (AD) was first described more than 100 years ago, we still have no treatment preventing the ongoing neurodegenerative process. Two major pathological hallmarks have been connected to AD: extracellular amyloid plaques (constituted by amyloid β-peptide – Aβ) and neurofibrillary tangles. Several biological processes have been shown to be altered in AD including mitochondrial functions, autophagosome formation and calcium (Ca2+) homeostasis. Interestingly, all these processes have been shown to be regulated in mitochondria-endoplasmic reticulum contact sites (MERCS). Moreover, both the activity and the number of these contacts are affected in AD, which could explain the alterations of the biological processes mentioned above. However, it is still unknown if the alteration in MERCS causes the pathology or vice-versa. In this thesis, I have contributed to uncovering some of the mechanisms behind the interplay between MERCS and AD. • In Study I we show that the number of MERCS is increased in brain biopsies of demented patients and that there is a reversed correlation between MERCS and Mini Mental State Examination (MMSE) scores. In the same study, we show that the number of MERCS positively correlate with aging and ventricular Aβ42 levels; • In Study II we show that Aβ increases the number of MERCS in different models, leading to alteration in autophagosome formation and mitochondrial function; • In Study III we show that the increase of MERCS, through acute knock-down of Mitofusin 2, leads to decreased levels of both Aβ40 and Aβ42 due to impaired g-secretase assembly and activity; • In Study IV we show that the translocase of the outer mitochondrial membrane (TOM) receptor protein TOM70 modulates Ca2+ shuttling from ER to mitochondria via IP3R3 at MERCS. Altogether, these studies contributed to unravel the role of MERCS in AD. We show that MERCS dynamics changes throughout ageing and is accentuated in AD pathology, affecting several biological processes vital for overall cellular function. We believe this increase of MERCS could either trigger the neurodegenerative processes underlying AD or being an attempt to rescue neuronal dysfunctions. Moreover, MERCS modulation affects Aβ levels, which makes us believe that MERCS and Aβ regulate each other in a reciprocal manner.
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