Biology subjects

Vecino, R.

Publications and source records attributed to Vecino, R..

3 recordsLinked to original sources

bioRxiv2026

APOE 4/4 promotes dysfunctional and inflammatory phenotypes concomitant with impaired maturation of hiPSC-derived astrocytes

Alzheimer's disease (AD) is the leading cause of dementia in the aging population, with the {varepsilon}4 allele of apolipoprotein E (APOE) being the strongest genetic risk factor. Although astrocytes are a major source of APOE, how APOE alleles affect astrocyte maturation and function remains unclear. We generated human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients carrying {varepsilon}3/{varepsilon}3 and {varepsilon}4/{varepsilon}4 alleles and from healthy controls (HC). We also used isogenic gene-edited hiPSC lines homozygous for each APOE allele and an APOE knock-out line to identify allele-specific phenotypes and distinguish gain- from loss-of-function mechanisms. APOE 4/4 astrocyte cultures showed significant reductions in GFAP- and S100{beta}-positive cell percentages compared to APOE 2/2 and APOE 3/3, with no changes in GLT-1- and AQP4-positive cells. Astrocytes of all genotypes responded to IL-1{beta} + TNF by increasing proinflammatory cytokine expression and release, and to both IL-1{beta} + TNF and A{beta}1-42 by changing morphology, with APOE 4/4 astrocytes showing increased IL6 mRNA and morphological branching upon IL-1{beta} + TNF stimulation. Notably, under basal conditions, APOE 4/4 astrocytes showed significant reductions in glutamate uptake capacity and cell size alongside increased IL-6 release and CXCL3 mRNA expression. In A{beta}1-42 uptake experiments, the proportion of A{beta}+ astrocytes was higher in APOE 4/4 than in APOE KO cultures. Most phenotypes were absent in APOE KO astrocytes, suggesting that the effects of APOE 4/4 were predominantly mediated through gain-of-function mechanisms. Our results indicate that APOE 4/4 alters astrocyte morphological and molecular maturation while promoting inflammation, disturbing glutamate and A{beta} handling under basal conditions. It suggests that APOE {varepsilon}4/{varepsilon}4 genotype disrupts astrocyte development and key processes of cellular homeostasis early in Alzheimer's disease etiopathology.

neuroscience↗

bioRxiv2024

GBA1 MUTATIONS ALTER THE PHENOTYPE AND BEHAVIOUR OF DOPAMINERGIC NEURONS IN PARKINSON DISEASE, INFLUENCING VGLUT2 AND CRYAB EXPRESSION

Mutations in the GBA1 gene are major risk factors for Parkinso[n]s disease (PD), but their role in PD pathology is not fully understood. The impact of GBA1 mutations was investigated in dopamine (DA) neurons obtained from induced pluripotent stem cells (iPSCs) derived from PD patients carrying the N370S or L444P GBA1 mutation. DA neurons co-expressing TH and VGLUT2 were detected in the cultures, and their number and/or expression of VGLUT2/SLC17A6 mRNA was markedly reduced in both N370S and L444P cultures compared to controls. A significant increase in the firing rate of N370S neurons was found, whereas evoked dopamine release was stronger from neurons carrying either mutation. Furthermore, mutant neurons accumulated abundant degenerative structures, and there was a significant accumulation of -synuclein aggregates in N370S neurons. Notably, a significant upregulation of the chaperone CRYAB/HSPB5/alpha-crystallin-B was found early in DA neuron differentiation and in the substantia nigra of PD patients. Our findings indicate that N370S and L444P GBA1 mutations impair midbrain DA neurons expressing VGLUT2, and provoke molecular, functional and structural changes, possibly involved in PD pathology.

neuroscience↗

bioRxiv2023

Presenilin-dependent regulation of tau pathology via the autophagy/proteasome pathway

Autosomal dominant inherited mutations in the presenilin (PS/PSEN) genes cause early-onset familial Alzheimers disease (AD) by enhancing cerebral accumulation of amyloid-{beta} (A{beta}) and microtubule-associated protein tau, although the precise cellular mechanisms by which PS dysfunction drives neuronal tau pathology remain still unclear. Here, we investigated the mechanisms linking PS/{gamma}-secretase-dependent tau pathology and autophagy by using molecular, imaging and pathological approaches in brains, fibroblasts and induced pluripotent stem cells (iPSCs)-derived neurons from mutant PSEN1 carriers, as well as in a novel tauopathy mouse model lacking PS in glutamatergic neurons. We found colocalization of phosphorylated tau with the autophagy marker p62 in the hippocampus of tauopathy patients with PSEN1 mutations, corticobasal degeneration and Picks disease. Remarkably, disrupted autophagic clearance of pathological tau was evidenced by increased autophagy markers and accumulation of total and AD-associated phosphorylated tau species (pTau 181, 202, 217) in hippocampal lysates and autophagosomes of familial AD-linked PSEN1 patients and PS-deficient tau transgenic mice. Human iPSC-derived neurons harboring the familial AD-linked PSEN1 G206D mutation are less sensitive to autophagy inhibition, reduce tau release and accumulate intracellular tau oligomers. Human primary fibroblasts from PSEN1 G206D and/or L286P carriers show elevated LC3 and autolysosomes indicating that these familial AD-linked PSEN1 mutations disrupt autophagy flux. PS is required for efficient autophagy-mediated tau degradation in neurons through a dual mechanism involving autophagy induction via blockage of Akt/PRAS40-dependent mTORC1 activation and promoting autophagosome/lysosome fusion. Surprisingly, pharmacological proteasome inhibition decreases tau accumulation in neurons by promoting tau release through a mechanism that requires functional PS. In conclusion, PS is required for autophagy/proteasome-mediated tau elimination in neurons, while familial AD-linked PSEN mutations cause progressive tau pathology by disrupting autophagy. These findings may impact on the development of new therapeutic targets for tauopathy dementias.

neuroscience↗