1. Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology.
- Author
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Gomez-Sequeda, Nicolas, Mendivil-Perez, Miguel, Jimenez-Del-Rio, Marlene, Lopera, Francisco, and Velez-Pardo, Carlos
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ALZHEIMER'S disease ,P53 antioncogene ,TAU proteins ,MIRROR neurons ,NEUROLOGICAL disorders ,NEURONS ,CANCER cell culture ,MEMBRANE potential - Abstract
Familial Alzheimer's disease (FAD) is a complex neurodegenerative disorder for which there are no therapeutics to date. Several mutations in presenilin 1 (PSEN 1), which is the catalytic component of γ-secretase complex, are causal of FAD. Recently, the p.Ile416Thr (I416T) PSEN 1 mutation has been reported in large kindred in Colombia. However, cell and molecular information from I416T mutation is scarce. Here, we demonstrate that menstrual stromal cells (MenSCs)-derived planar (2D) PSEN 1 I416T cholinergic-like cells (ChLNS) and (3D) cerebral spheroids (CSs) reproduce the typical neuropathological markers of FAD in 4 post-transdifferentiating or 11 days of transdifferentiating, respectively. The models produce intracellular aggregation of APPβ fragments (at day 4 and 11) and phosphorylated protein TAU at residue Ser
202 /Thr205 (at day 11) suggesting that iAPPβ fragments precede p-TAU. Mutant ChLNs and CSs displayed DJ-1 Cys106 -SO3 (sulfonic acid), failure of mitochondria membrane potential (ΔΨm ), and activation of transcription factor c-JUN and p53, expression of pro-apoptotic protein PUMA, and activation of executer protein caspase 3 (CASP3), all markers of cell death by apoptosis. Moreover, we found that both mutant ChLNs and CSs produced high amounts of extracellular eAβ42 . The I416T ChLNs and CSs were irresponsive to acetylcholine induced Ca2+ influx compared to WT. The I416T PSEN 1 mutation might work as dominant-negative PSEN1 mutation. These findings might help to understanding the recurring failures of clinical trials of anti-eAβ42 , and support the view that FAD is triggered by the accumulation of other intracellular AβPP metabolites, rather than eAβ42. [ABSTRACT FROM AUTHOR]- Published
- 2023
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