Biology subjects

Rodriguez-Alvarez, J.

Publications and source records attributed to Rodriguez-Alvarez, J..

4 recordsLinked to original sources

bioRxiv2025

Transcriptional and synaptic regulation of NMDA glutamate receptor-mediated hippocampal plasticity and memory

Synapse-to-nucleus signaling regulates activity-dependent synaptic plasticity underlying memory by linking N-methyl-D-aspartate (NMDA) glutamate receptors (GluN) to gene transcription mediated by the transcription factor cAMP-response element binding protein (CREB), but the underlying gene programs mediating potentiation at excitatory synapses are unknown. Here, we analyzed genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) datasets of mouse and human CREB and the synaptonuclear factor CREB-regulated transcription coactivator1 (CRTC1) to identify relevant target genes and biological pathways coupling neuronal activity to synaptic function/plasticity. Our analyses indicate that CRTC1 specifically couples neuronal activity with synaptic plasticity by binding to conserved promoters of CREB target genes comprising inducible transcription factors (including c fos, Crem, Npas4 and Nr4a1-3), and neuronal excitability and plasticity genes, including Ntrk2, Homer1, Dlg4 (PSD-95) and the NMDA receptor subunit Grin1 (GluN1). CRTC1/CREB target genes were highly enriched in gene ontology (GO) nuclear terms, including several members of the CREB family, and transcriptional modulators and repressors. Interestingly, GO enrichment and protein-protein interaction (PPI) network analyses revealed that genes mediating synapse-to-nucleus signaling (including most known synaptonuclear factors and direct interacting modulators) are collectively regulated by CREB/CRTC1, and that protein kinase C (PKC) is a key interactor of the CRTC1/14-3-3 complex at synapses. In agreement with these in silico analyses, we show that CRTC1 regulates synaptic activity-dependent phosphorylation and synaptic recruitment of GluN1 mediated by PKC in hippocampal neurons, and that PKC activation reverses NMDA receptor-mediated currents and long-term potentiation (LTP) deficits caused by CRTC1 silencing in the hippocampus. Consistent with genomics and functional data, morphological and behavioral analyses show crucial roles of CRTC1 on dendritic spine structure, plasticity, and hippocampal-dependent associative memory. Our results support a model in which neuronal activity and synaptic inputs are integrated in the nucleus through conserved CREB/CRTC1-regulated transcriptional programs sustaining global synapse-to-nucleus signaling pathways impacting on synaptic plasticity and memory.

neuroscience↗

bioRxiv2024

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE

The ketogenic diet, characterized by high fat and low carbohydrates, has gained popularity not only as a strategy for managing body weight but also for its efficacy in delaying cognitive decline associated with neurodegenerative diseases and the aging process. Since this dietary approach stimulates the livers production of ketone bodies, primarily {beta}-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons, we investigated whether BHB could mitigate impaired AMPA receptor trafficking, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as saturated fatty acids. Here, we observe that, in cultured primary cortical neurons, exposure to palmitic acid (200M) decreased surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids, such as oleic acid and {omega}-3 docosahexaenoic acid (200M), and BHB (5mM) increased them. Furthermore, BHB countered the adverse effects of palmitic acid on synaptic GluA1 levels in hippocampal neurons, as well as excitability and plasticity in hippocampal slices. Additionally, daily intragastric administration of BHB (100 mg/kg/day) for two months reversed cognitive impairment induced by a saturated high-fat diet (49% of calories from fat) in a mouse experimental model of obesity. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptors abundance, synaptic function and neuroplasticity, shedding light on the potential use of BHB to delay cognitive impairments associated with metabolic diseases.

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↗

bioRxiv2023

Differential neural circuit vulnerability to β-amyloid and tau pathologies in novel Alzheimer disease mice

Alzheimers disease (AD) progresses with memory loss and neuropsychiatric symptoms associated with cell specific vulnerability in memory- and emotion-related neural circuits. Neuropathological and synaptic changes are key factors influencing the clinical progression to dementia, but how they cooperate to cause memory and emotional disturbances is largely unknown. Here, we employed pathological, behavioral, expansion microscopy, electrophysiology and transcriptomic approaches to evaluate the effects of amyloid-{beta} (A{beta}) and tau on neuropathological progression, synaptic function, and memory and emotional symptoms in amyloid precursor protein (APP), Tau and double novel APP/Tau transgenic mice expressing the mutant human amyloid precursor protein (APPSw,Ind) and/or microtubule-associated protein tau (MAPT) in excitatory neurons. APP/Tau mice of both sexes show spatial learning and memory deficits associated with synaptic tau accumulation and reduced synaptic proteins and neurotransmission in the hippocampus. By contrast, male and female APP/Tau mice exhibit innate anxious behavior and impaired fear memory extinction linked to A{beta} pathology and with absence of synaptic tau in the basolateral amygdala (BLA). Intriguingly, APP/Tau mice show NMDA-dependent long-term potentiation (LTP) deficits in the hippocampus but not in the amygdala. Bulk RNA sequencing reveals region-specific but also common transcriptional changes in response to A{beta}/tau pathology, including downregulation of synapse transmission and ion channel activity genes. Importantly, we detected 65 orthologs of human AD risk genes identified in GWAS (e.g., APOE, BIN1, CD33, CLU, PICALM, PLCG2, PTK2B, TREM2, SORL1, USP6NL) differentially expressed in the hippocampus and/or BLA of APP/Tau mice, indicating that this APP/Tau model exhibits transcriptional alterations linked to known molecular determinants of AD development. In conclusion, simultaneous development of A{beta} and tau neuropathologies in this double APP/Tau transgenic mouse model reproduces synaptic, behavioral, and molecular alterations associated with AD pathophysiology in a region-specific manner. Our findings highlight region-specific pathological effects of A{beta} and tau in excitatory neuronal circuits mediating emotional and memory processing, providing evidence that both factors and their molecular cascades should be considered in future AD preventive and therapeutic strategies. Graphical abstractAge-dependent vulnerability of memory and emotional neural circuits in response to tau and A{beta} pathologies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/536603v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@efbe90org.highwire.dtl.DTLVardef@1c7f1dborg.highwire.dtl.DTLVardef@1d7764borg.highwire.dtl.DTLVardef@9738ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗