Biology subjects

Pina-Crespo, J.

Publications and source records attributed to Pina-Crespo, J..

3 recordsLinked to original sources

bioRxiv2026

Spatial proximity to AD pathology defines cell-type and genotype-specific characteristics in human AD hippocampus

How amyloid-{beta} (A{beta}) plaques and tau phosphorylation spatially relate to cell response and genetic variation in Alzheimer's disease (AD) brain is currently unclear. We established a pipeline to concurrently annotate A{beta} and AT8 ptau pathology and cell-specific MERFISH expression profiles in human control and AD hippocampus. We characterized expression signatures in glia and neurons proximal or distal to A{beta} plaques, AT8 ptau-enriched neurons, or A{beta} and AT8 ptau in combination, and used spatially-defined transcriptional signatures to infer pathology-associated states in large snRNA-seq datasets lacking spatial context. We characterized variants from 120 gene loci associated with AD risk that affect cell-specific gene expression within local pathological contexts. Astrocyte APOE4/E4 expression was specifically suppressed in proximity to A{beta} plaques, whereas other APOE genotypes were unaffected by A{beta} proximity. Together, this analysis pipeline couples expression profiles in proximity to A{beta} and tau pathology, and implicates AD cis-gene variants with spatial sensitivity to AD pathology.

neuroscience↗

bioRxiv2023

S-Nitrosylation of CRTC1 in Alzheimer's disease impairs CREB-dependent gene expression induced by neuronal activity

CREB-regulated transcription coactivator 1 (CRTC1) plays an important role in synaptic plasticity, learning and long-term memory formation through regulation of neuronal activity-dependent gene expression, and CRTC1 dysregulation is implicated in Alzheimers disease (AD). Here, we show that increased S-nitrosylation of CRTC1 (forming SNO-CRTC1), as seen in cell-based, animal-based, and human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neuron-based AD models, disrupts its binding with CREB and diminishes the activity-dependent gene expression mediated by the CRTC1/CREB pathway. We identified Cys216 of CRTC1 as the primary target of S-nitrosylation by nitric oxide (NO)-related species. Using CRISPR/Cas9 techniques, we mutated Cys216 to Ala in hiPSC-derived cerebrocortical neurons bearing one allele of the APPSwe mutation (AD-hiPSC neurons). Introduction of this non-nitrosylatable CRTC1 construct rescued defects in AD-hiPSC neurons, including decreased neurite length and increased neuronal cell death. Additionally, expression of non-nitrosylatable CRTC1 in vivo in the hippocampus rescued synaptic plasticity in the form of long-term potentiation (LTP) in 5XFAD mice. Taken together, these results demonstrate that formation of SNO-CRTC1 contributes to the pathogenesis of AD by attenuating the neuronal activity-dependent CREB transcriptional pathway, and suggests a novel therapeutic target for AD.

neuroscience↗

bioRxiv2022

Targeted protein S-nitrosylation of ACE2 as potential treatment to prevent spread of SARS-CoV-2 infection

Prevention of infection and propagation of SARS-CoV-2 is of high priority in the COVID-19 pandemic. Here, we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 Spike protein, thereby inhibiting viral entry, infectivity, and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and thus spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E-protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model, and thus provide a novel avenue for therapy.

microbiology↗