E-cadherin controls a wide array of cellular behaviors including cell-cell adhesion, differentiation and tissue development. Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, controls a gamma-secretase-like cleavage of E-cadherin. This cleavage is stimulated by apoptosis or calcium influx and occurs between human E-cadherin residues Leu731 and Arg732 at the membrane-cytoplasm interface. The PS1/gamma-secretase system cleaves both the full-length E-cadherin and a transmembrane C-terminal fragment, derived from a metalloproteinase cleavage after the E-cadherin ectodomain residue Pro700. The PS1/gamma-secretase cleavage dissociates E-cadherins, beta-catenin and alpha-catenin from the cytoskeleton, thus promoting disassembly of the E-cadherin-catenin adhesion complex. Furthermore, this cleavage releases the cytoplasmic E-cadherin to the cytosol and increases the levels of soluble beta- and alpha-catenins. Thus, the PS1/gamma-secretase system stimulates disassembly of the E-cadherin- catenin complex and increases the cytosolic pool of beta-catenin, a key regulator of the Wnt signaling pathway.
Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by c-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at ADrelated residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway. IntroductionIncreased neuronal cell death, tau overphosphorylation and accumulation of neurofibrillary tangles (NFTs) and amyloid plaques are the main pathological hallmarks of Alzheimer's disease (AD) brains. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in the transmission of survival signals in a wide range of cell types including neurons (for reviews, see Chan et al, 1999;Brunet et al, 2001). PI3K activates its downstream effector Akt/protein kinase B (Akt) by promoting its phosphorylation at residues serine 473 (Ser473) and threonine 308 (Thr308). Activated Akt, in turn, phosphorylates a wide range of substrates activating anti-apoptotic (survival) factors and inactivating pro-apoptotic factors (Brunet et al, 2001). The PI3K/Akt pathway is activated following recruitment of PI3K to the plasma membrane in response to a number of extracellular stimuli including growth factors (Brunet et al, 2001) and cadherin homophilic cell-cell adhesions, which result in the recruitment of PI3K to adhesion complexes (Pece et al, 1999;Kovacs et al, 2002;Tran et al, 2002;Yap and Kovacs, 2003). Akt downregulates the activities of glycogen synthase kinases 3a (GSK-3a) and 3b (GSK-3b) by phosphorylating the former at residue serine 21 (Ser21) and the latter at residue serine 9 (Ser9) (Cross et al, 1995;Kaytor and Orr, 2002). Increased GSK-3b activity has been implicated in neuronal cell death (Pap and Cooper, 1998;Hetman et al, 2000;Cross et al, 2001;Lucas et al, 2001) and tau overphosphorylation (Hanger et al, 1992;Hong et al, 1997;Pei et al, 1999;Lucas et al, 2001), while GSK-3a was recently implicated in the production of Ab peptide, the principal protein component of amyloid plaques (Phiel et...
Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with neurological and neuropsychiatric illness in many individuals. We sought to further our understanding of the relationship between brain tropism, neuro-inflammation, and host immune response in acute COVID-19 cases. Methods Three brain regions (dorsolateral prefrontal cortex, medulla oblongata, and choroid plexus) from 5 patients with severe COVID-19 and 4 controls were examined. The presence of the virus was assessed by western blot against viral spike protein, as well as viral transcriptome analysis covering > 99% of SARS-CoV-2 genome and all potential serotypes. Droplet-based single-nucleus RNA sequencing (snRNA-seq) was performed in the same samples to examine the impact of COVID-19 on transcription in individual cells of the brain. Results Quantification of viral spike S1 protein and viral transcripts did not detect SARS-CoV-2 in the postmortem brain tissue. However, analysis of 68,557 single-nucleus transcriptomes from three distinct regions of the brain identified an increased proportion of stromal cells, monocytes, and macrophages in the choroid plexus of COVID-19 patients. Furthermore, differential gene expression, pseudo-temporal trajectory, and gene regulatory network analyses revealed transcriptional changes in the cortical microglia associated with a range of biological processes, including cellular activation, mobility, and phagocytosis. Conclusions Despite the absence of detectable SARS-CoV-2 in the brain at the time of death, the findings suggest significant and persistent neuroinflammation in patients with acute COVID-19.
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