Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal sAPPβ fragments accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ dysregulation: Therapeutic implications

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies. Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intracellular soluble amyloid precursor protein (sAPPf) fragments and extracellular Aβ42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys 106-SH into DJ-1Cys 106-SO 3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca 2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the

Nutritional assessment in patients with early-onset Autosomal Dominant Alzheimer’s Disease due to PSEN1- E280A genetic variant: a cross-sectional study

“…The frequency of multimorbidity, polymedication, and frailty in our sample was consistent with the prevalence of the same geriatric syndromes in older patients (51). An in-vitro study of our group in carriers of the same E280A genetic variant found that cholinergic neurons (differentiated from multipotent mesenchymal cells) display high levels of reactive oxygen species, loss of mitochondrial membrane potential and DNA fragmentation unlike other mesenchymal-derived cells (52). Therefore, to date, we cannot attribute the similarities between the geriatric syndromes in our middle-aged adults and older people only to the genetic variant.…”

Multi-Target Effects of the Cannabinoid CP55940 on Familial Alzheimer’s Disease PSEN1 E280A Cholinergic-Like Neurons: Role of CB1 Receptor

“…3A, C). Cell death by apoptosis is a prominent feature in 464 mutant ChLNs [16]. We used, therefore, the acti- Effectively, we confirmed that ChLNs displayed high levels of protein c-Jun (Fig.…”

“…Since PSEN1 E280A ChLNs response to ACh decline in a time-dependent fashion [16], and since SR alone treatment was innocuous for WT and E280A ChLNs, we evaluated whether early inhibi- (Fig. 8H).…”

Latent Tri-lineage Potential of Human Menstrual Blood–Derived Mesenchymal Stromal Cells Revealed by Specific In Vitro Culture Conditions

“…The stromal cell-based disease model provides a platform for a better understanding of human neurodegenerative disease mechanisms (e.g., [19]) and the potential discovery of innovative therapeutics (e.g., [20]). As primary human neurons from living subjects are normally not accessible to researchers, there is a pressing need for an alternative source of authentic human neurons which allows modeling of neurodegeneration in vitro.…”