Biology subjects

Saura, C. A.

Publications and source records attributed to Saura, C. A..

4 recordsLinked to original sources

bioRxiv2024

Nr4a2 blocks oAbeta-mediated synaptic plasticity dysfunction and ameliorates spatial memory deficits in the APPSw,Ind mouse

Alzheimers disease AD is associated with disruptions in neuronal communication, especially in brain regions crucial for learning and memory, such as the hippocampus. The amyloid hypothesis suggests that the accumulation of amyloid-beta oligomers (oA{beta}) contributes to synaptic dysfunction by internalisation of synaptic AMPA receptors. Recently, it has been reported that Nr4a2, a member of the Nr4a family of orphan nuclear receptors, plays a role in hippocampal synaptic plasticity by regulating BDNF and synaptic AMPA receptors. Here, we demonstrate that oA{beta} inhibits activity-dependent Nr4a2 activation in hippocampal neurons, indicating a potential link between oA{beta} and Nr4a2 down-regulation. Furthermore, we have observed a reduction in Nr4a2 protein levels in postmortem hippocampal tissue samples from early AD stages. Pharmacological activation of Nr4a2 proves effective in preventing oA{beta}-mediated synaptic depression in the hippocampus. Notably, Nr4a2 overexpression in the hippocampus of AD mouse models ameliorates spatial learning and memory deficits. In conclusion, the findings suggest that oA{beta} may contribute to early cognitive impairment in AD by blocking Nr4a2 activation, leading to synaptic dysfunction. Thus, our results further support that Nr4a2 activation is a potential therapeutic target to mitigate oA{beta}-induced synaptic and cognitive impairments in the early stages of Alzheimers disease.

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↗

bioRxiv2022

Spatial memory training reverses GirK channels modulation in the transgenic APPSw,Ind Alzheimer's disease mouse model

Alzheimers disease (AD) is a dementia characterized by progressive memory decline and neurodegeneration caused by the accumulation of amyloid-{beta} (A{beta}) peptides. Last findings point to an imbalance between excitatory and inhibitory neurotransmission as the initial impairment in early stages, and the hippocampus as one of the most susceptible brain areas. The G-protein-gated inwardly rectifying potassium (GirK) channel has been proposed as a potential target to restore excitatory/inhibitory balance in amyloidosis models. Moreover, cognitive training may counteract early AD symptoms, although its effect on GirK channels remains unknown. Here, the effect of genotype, age, and training in a hippocampal-dependent memory task on the protein expression of GirK subunits and modulators were studied using APPSw,Ind mice. Results showed a reduction of GirK2 expression as well as an increased expression of SNX27 in the hippocampus of 6-month-old APPSw,Ind mice. Training in a memory task restored GirK2 and SNX27 levels. Thus, the effect of A{beta} on GirK2 could account for the excitatory/inhibitory imbalance transmission found in AD models, and training in a cognitive hippocampal-dependent task reverses this effect and lessens early A{beta}-dependent AD deficits. Summary statementA{beta} decreases hippocampal GirK2 expression in APPSw,Ind mice, which could contribute to early hyperexcitability found in Alzheimers disease models. Training in spatial memory tasks has shown to counteract this reduction.

neuroscience↗