Biology subjects

Molina-Porcel, L.

Publications and source records attributed to Molina-Porcel, L..

7 recordsLinked to original sources

bioRxiv2025

Biomarkers in cerebrospinal fluid sediments

Cerebrospinal fluid (CSF) biomarkers for neurodegenerative diseases have been extensively studied over the years. However, CSF samples are routinely centrifuged, and the resulting sediment or pellet is typically discarded to remove cellular debris and high-density particles. This standard practice raises a critical question: could these discarded sediments harbour potential biomarkers relevant to the diagnosis and prognosis of certain brain diseases? In this study, we analysed CSF pellets from various cases and identified, entrapped among undetermined remnants, brain-derived structures such as wasteosomes and psammoma bodies. Furthermore, we observed that disease-relevant proteins can become deposited in the sediment, as is the case for both tau and A{beta}42 in Alzheimers disease or tau in progressive supranuclear palsy disease. These findings suggest that some potential biomarkers might accumulate or be hidden in the sediment and, taken as a whole, the results underscore the need to broaden the scope of biomarker research. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/657984v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1d5b55corg.highwire.dtl.DTLVardef@175ae02org.highwire.dtl.DTLVardef@f30e42org.highwire.dtl.DTLVardef@12d326b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

neuroscience↗

bioRxiv2025

Pre-amyloid cognitive intervention preserves brain function in aged TgF344-AD rats, maintaining connectivity and enhancing plasticity in a sex-specific manner

BackgroundAlzheimers disease is characterized by progressive cognitive decline and neurodegeneration, with cognitive reserve playing a key role in mitigating disease impact. Cognitive stimulation has been suggested as a non-pharmacological approach to enhance cognitive reserve and delay cognitive deterioration, but its underlying mechanism remains to be fully understood. This study investigates the effects of pre-amyloid cognitive intervention on brain connectivity, memory, synaptic plasticity and neuroinflammation in aged TgF344-AD rats, considering sex-specific differences. MethodsMale and female TgF344-AD and wild-type rats were assigned to trained and untrained groups, with cognitive stimulation administered through repetitive delayed nonmatch-to-sample tasks. Longitudinal magnetic resonance imaging acquisitions assessed training-induced changes in whole-brain functional connectomics and in particular entorhinal cortex connectivity. Memory was evaluated using the novel object recognition test. Cellular analysis of neurons (NeuN+, Parvalbumin+) and microglial cells, as well as molecular (PSD95, TrkB, p-RPS6, and VGLUT) analyses were conducted to determine the role of cognitive stimulation in modulating neuronal density, neuroinflammation and neuroplasticity. ResultsMale TgF344-AD rats undergoing prolonged cognitive stimulation had preserved global functional connectivity and exhibited improved recognition memory, compared to untrained animals, while TgF344-AD females did not follow this pattern. Entorhinal cortex connectivity was significantly loss in 19-month-old rats compared to wild-type rats and this was completely prevented by training. At a cellular level, cognitive stimulation significantly decreased the number of PV+ neurons in the dentate gyrus of trained rats. Moreover, a greater microglial density around A{beta} plaques and a less reactive phenotype was clearly observed at 11 in trained rats. These protective effects diminished by 19 months, coinciding with increased neuroinflammation and microglial dysfunction. At a molecular level, cognitive stimulation preserved PSD95 expression in male TgF344-AD and p-RPS6 in both sexes. ConclusionsPre-amyloid cognitive stimulation enhances synaptic plasticity, sustains brain network integrity, and modulates neuroinflammation, contributing to increased resilience against Alzheimers disease-related cognitive decline. In general, cognitive stimulation exerted a more protective effect in male TgF344-AD rats showing sex-dependent differences in pathology and cognitive reserve mechanisms. These findings highlight the importance of early cognitive engagement as a potential strategy to delay disease onset and underscore sex-specific differences in cognitive resilience mechanisms.

neuroscience↗

bioRxiv2023

Mitochondrial complex I deficiency stratifies idiopathic Parkinson's disease

Idiopathic Parkinsons disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.

neuroscience↗

bioRxiv2021

Long-term decreased cannabinoid type-1 receptor activity restores specific neurological phenotypes in the Ts65Dn mouse model of Down syndrome

Intellectual disability is the most prevalent and limiting hallmark of Down syndrome (DS), without any pharmacological treatment available. Neurodegeneration and neuroinflammation are relevant neurological features of DS reaching to early development of Alzheimers disease. Preclinical evidence suggests that the endocannabinoid system, an important neuromodulator on cognition and neuroinflammation, could act as beneficial target in DS. Indeed, cannabinoid type-1 receptor (CB1R) activity was enhanced in the hippocampus of young-adult trisomic Ts65Dn mice, a well-characterized surrogate model of DS. In previous studies, inhibition of CB1R, was able to restore key neurological deficits in this mouse model. To determine the possible clinical relevance of this target, it is mandatory to evaluate the long-term consequences of attenuated CB1R activity and to minimize the possible side-effects associated to this mechanism. We found that CB1R expression was significantly enhanced in the hippocampus brains of aged DS subjects. Similarly, middle-aged trisomic mice showed enhanced CB1R expression. Long-term oral administration of a low dose of the CB1R specific antagonist rimonabant was administered to male and female Ts65Dn trisomic and wild-type mice from the time of weaning to 10 months, an age when signs of neurodegeneration have been described in the model. CB1R inhibition resulted in significant cognitive improvement in novel object-recognition memory in trisomic male and female mice, reaching a similar performance to that of wild-type littermates. Interestingly, this long-term rimonabant treatment modify locomotor activity, anxiety-like behavior, body weight or survival rates. Brain analysis at 10 months of age revealed noradrenergic and cholinergic neurodegeneration signs in trisomic mice that were not modified by the treatment, although the alterations in hippocampal microglia morphology shown by vehicle-treated trisomic mice was normalized in trisomic mice exposed to rimonabant. Altogether, our results demonstrate a sustained pro-cognitive effect of CB1R inhibition at doses that do not produce major side effects that could be associated to an anti-inflammatory action, suggesting a potential interest in this target of to preserve cognitive functionality in DS.

neuroscience↗

bioRxiv2020

Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. A major neuropathological finding in ALS is the coexistence of glial activation and aggregation of the phosphorylated transactive response DNA-binding protein 43-kDa (pTDP43) in the motor cortex at the earliest stages of the disease. Despite this, the transcriptional alterations associated with these pathological changes in this major vulnerable brain region have yet to be fully characterized. Here, we have performed massive RNA sequencing of the motor cortex of ALS (n=11) and healthy controls (HC; n=8). We report extensive RNA expression alterations at gene and isoform levels, characterized by the enrichment of neuroinflammatory and synapse related pathways. The assembly of gene co-expression modules confirmed the involvement of these two principal transcriptomic changes, and showed a strong negative correlation between them. Furthermore, cell-type deconvolution using human single-nucleus RNA sequencing data as reference demonstrated that microglial cells are overrepresented in ALS compared to HC. Importantly, we also show for the first time in the human ALS motor cortex, that microgliosis is mostly driven by the increased proportion of a microglial subpopulation characterized by gene markers overlapping with the recently described disease associated microglia (DAM). Using immunohistochemistry, we further evidenced that this microglial subpopulation is overrepresented in ALS and that variability in pTDP43 aggregation among patients negatively correlates with the proportion of microglial cells. In conclusion, we report that neuroinflammatory changes in ALS motor cortex are dominated by microglia which is concomitant with a reduced expression of postsynaptic transcripts, in which DAM might have a prominent role. Microgliosis therefore represents a promising avenue for therapeutic intervention in ALS.

neuroscience↗

bioRxiv2019

Assessing circular RNAs in Alzheimer disease

Circular RNAs (circRNA) are evolutionary conserved non-coding RNAs resulting from the backsplicing of precursor messengers. Recently, a circular-transcriptome-wide study of circRNA in brain tissue from patients with Alzheimers disease (AD) has revealed a striking association between the expression of circRNA and AD pathological diagnosis. In the present study, we aimed at replicating the major findings in an independent case series comprising definitive sporadic and familial AD. In order to assess the specificity of circRNA changes, we also included cases with frontotemporal lobar degeneration (FTLD), comprising brain specimens with TDP-43 aggregates (FTLD-TDP43) and samples that presented Tau accumulation (FTLD-Tau). Through a quantitative PCR approach, we evaluated a total of eight circRNAs that surpassed the significant threshold in the former meta-analysis (circHOMER1, circDOCK1, circKCNN2, circMAN2A1, circFMN1, circRTN4, circMAP7, and circPICALM). Average expression changes between AD patients and controls followed the same directions as previously reported, suggesting an overall upregulation of circDOCK1, circMAP7, circMAN2A1, circRTN4 and circPICALM, and a downregulation of the remainder (circHOMER1, circFMN1 and circKCNN2) in AD brain tissue. We also confirmed an exacerbated alteration in circRNA expression in the Mendelian AD group compared to the sporadic forms. Two circRNAs, circHOMER1 and circKCNN2, also showed significant expression alterations in the group of FTLD-Tau and FTLD-TDP43, respectively. Overall, these results reinforce the conception that expression of circRNAs is altered in Alzheimers disease, and also suggest a wider involvement of this particular class of RNA in other neurodegenerative dementias.

genomics↗

bioRxiv2019

Neuropathological validation of the MDS-PSP criteria with PSP and other frontotemporal lobar degeneration

BackgroundProgressive supranuclear palsy (PSP) is clinically heterogeneous. Clinical diagnostic criteria were revised in 2017, to increase sensitivity and operationalize the diagnosis of PSP Richardsons syndrome (PSP-RS) and \"variant\" syndromes (vPSP).\n\nObjectivesTo determine the (1) sensitivity and specificity of the 1996 NINDS-SPSP and 2017 MDS-PSP criteria; (2) false positive rates in frontotemporal dementia with frontotemporal lobar degeneration (FTLD); and (3) clinical evolution of variant PSP syndromes (vPSP).\n\nMethodsRetrospective multicenter review of 108 neuropathologically-confirmed PSP patients and 81 patients with other forms of FTLD: 38 behavioral variant frontotemporal dementia (bvFTD), 14 non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), and 29 corticobasal degeneration (CBD), Sensitivity and specificity of the MDS-PSP criteria were compared to the NINDS-SPSP criteria at baseline. In a subset of cases, the timing and frequency of clinical features were compared across groups over six years.\n\nResultsSensitivity for recognition of probable and possible PSP pathology was higher by MDS-PSP criteria (72.2-100%) than NINDS-SPSP criteria (48.1-61.1%). Specificity was higher by NINDS-SPSP criteria (97.5-100%) than MDS-PSP criteria (53.1-95.1%). False positives by MDS-PSP criteria were few for bvFTD (10.5-18.4%) but common for CBD and nfvPPA (fulfilling \"suggestive of PSP). Most vPSP cases developed PSP-RS-like features within six years, including falls and supranuclear gaze palsy, distinguishing frontal presentations of PSP from bvFTD, and speech/language presentations of PSP from nfvPPA.\n\nConclusionsThe 2017 MDS-PSP criteria successfully identify PSP, including variant phenotypes. This independent validation of the revised clinical diagnostic criteria strengthens the case for novel therapeutic strategies against PSP to include variant presentations.

neuroscience↗