Biology subjects

Lopera, F.

Publications and source records attributed to Lopera, F..

6 recordsLinked to original sources

bioRxiv2026

Astrocyte-driven small vessel disease is an early, amyloid-independent feature of PSEN1 E280A familial Alzheimer's disease

Cerebral Small vessel disease (cSVD) is a prevalent feature of Alzheimers disease (AD) pathology. Whether this pathology is a late consequence of amyloid and tau accumulation or an early, direct effect of PSEN1 dysfunction has remained unresolved. We found that it is more severe in familial AD (FAD) caused by E280A mutation in presenilin 1 (PSEN1). These cases present with a distinctive proteomic signature, associated with pathological features, more dysregulated in the occipital cortex (OC) compared to the frontal cortex (FC), and characterized by multiple dysregulated proteins involved in extracellular matrix (ECM) and RNA-associated processes. This proteomic fingerprint was associated with abnormal collagen build up, ECM disorganization, and signatures of aberrant angiogenesis. Six months old transgenic knock-in mice homozygous for Psen1 E280A mutation (PSEN1Ki) also showed a similar phenotype with microvascular tortuosity and proteomic changes. Critically, these mice develop neither A{beta} plaques nor tau tangles, indicating that the shared microvascular and RNA-associated changes are direct consequences of PSEN1 dysfunction rather than downstream effects of amyloid pathology. Remarkably, dysregulated RNA-associated protein networks overlapped between FAD and PSEN1Ki mice. Cerebral microvessels microstructure in PSEN1Ki mice at two months and six months showed abnormal astrocytic end-feet with lamellar deposits implicating blood-brain barrier damage. Finally, single nuclei transcriptomic analysis of AD patients and controls showed similar abnormal astrocytes in both sporadic and familial variants, but FAD astrocytes expressed dysregulated genes identified in the proteomic analyses, such as GLUL, APOE, and CLU. Our findings suggest that cSVD is an early pathological event in PSEN1 FAD and that is driven by abnormal RNA-associated processes and astrocytic dysfunction.

neuroscience↗

bioRxiv2025

Serum Lipidome as an Early Peripheral Indicator in Familial Alzheimers Disease

Protein biomarkers in biofluids are highly sensitive indicators of prodromal cognitive impairment yet remain limited for primary prevention. Lipids, essential to brain structure and function, offer untapped prognostic value. Here, we identify a lipidomic signature in serum from asymptomatic PSEN1-E280A mutation carriers aged 6-40 years, that differentiate carriers from non-carriers with an AUC 80-90%. Similarly, to symptomatic carriers ([≥]41 years; 93%) and sporadic AD cases (85%), using high-resolution mass spectrometry. Latent profile analysis revealed lipid-based signatures of dementia risk and resilience, shaped by genotype, sex, and APOE isoform, and supported by SIMOA protein biomarkers. Age-dependent dysregulation in sphingolipid and glycolipid metabolism was validated by enzymatic activity (TLC), glial phenotyping (flow cytometry), and gene expression (snRNAseq) in postmortem brain. Ganglioside clearance deficits emerged by age 6-12, followed by proinflammatory shifts from age 13 and p-tau217 elevation by age 20, with greater burden in females and APOE4 carriers. APOE3Ch individuals showed differential salvage pathways of ceramides and gangliosides. These findings position early lipid pathway dysregulation as a biological contributor to Alzheimers pathogenesis and a potential therapeutic target for primary prevention.

neuroscience↗

bioRxiv2023

Reproducible Neuronal Components found using Group Independent Component Analysis in Resting State Electroencephalographic Data

ObjectiveEvaluate the reliability of neural components obtained from the appli-cation of the group ICA (gICA) methodology to resting-state EEG datasets acquired from multiple sites. MethodsFive databases from three sites, covering a total of 292 healthy subjects, were analyzed. Each dataset was segmented into groups of 15 subjects, for a total of 19 groups. Data were pre-processed using an automatic pipeline leveraging robust average referencing, wavelet-ICA and automatic rejection of epochs. On each group, stable gICA decompositions were calculated using the ICASSO methodology through a range of orders of decompositions. Each order was characterized by reliability and neuralness metrics, which were evaluated to select a single order of decomposition. Finally, using the decompositions of the selected order, a clustering analysis was performed to find the common components across the 19 groups. Each cluster was characterized by the mean scalp map, its dipole generator with its localization in Talairach coordinates, the spectral behavior of the associated time-series of the components, the assigned ICLabel class and metrics that reflected their reproducibility. ResultsLower order of decompositions benefits the gICA methodology. At this, using an order of ten, the number of reproducible components with high neuronal information tends to be around nine. Of these, the bilateral motor, frontal medial, and occipital neuronal components were the most reproducible across the different datasets, appearing in more than 89% of the 19 groups evaluated. ConclusionWe developed a workflow that allows finding reproducible spatial filters between different data sets. This contributes to the improvement of the spatial resolution of the EEG as a brain mapping technique.

neuroscience↗

bioRxiv2022

Signatures for Viral Infection and Inflammation in the Proximal Olfactory System in Familial Alzheimer's Disease

ObjectiveAlzheimers disease (AD) is characterized by loss of smell and olfactory system pathology that precedes the diagnosis of dementia. Understanding these early processes can potentially identify diagnostic and therapeutic targets to slow AD progression. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and olfactory tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A paisa mutation and age-matched controls. MethodsFormalin-fixed, paraffin-embedded sections containing both the OB and OT from 6 FAD individuals and 6 age-matched controls were obtained. Tissue morphology and composition were characterized by immunohistochemistry using antibodies against the myelin marker proteolipid protein (PLP), amyloid-beta (A{beta}), and microglia/macrophage markers Iba1 and CD68, respectively. OB and OT were analyzed separately by targeted RNA sequencing of the whole human transcriptome (BioSpyder TempO-Seq); ingenuity pathway analysis and R-computational program were used to identify differentially expressed genes and pathways between groups. The nanoString spatial proteomics assay for 88 proteins, including markers for AD and immune responses, was used to complement gene expression findings. ResultsCompared to control OT, FAD OT had significantly increased immunostaining for A{beta} and CD68 in the high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region only; both control and FAD OT samples had similar total area of high and low myelinated regions. In FAD samples, RNA sequencing showed a transcription profile consistent with: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts, indicating dysregulation of myelination. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. ConclusionsThese findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt downstream hippocampal function, contributing to acceleration of FAD progression.

neuroscience↗

bioRxiv2021

Amyloid-β and tau pathologies relate to distinctive brain dysconnectomics in preclinical autosomal-dominant Alzheimer's disease

The human brain is composed of functional networks that have a modular topology, where brain regions are organized into communities that form internally dense (segregated) and externally sparse (integrated) subnetworks that underlie higher-order cognitive functioning. It is hypothesized that amyloid-{beta} and tau pathology in preclinical Alzheimers disease (AD) spread through functional networks, disrupting neural communication that results in cognitive dysfunction. We used high-resolution (voxel-level) graph-based network analyses to test whether in vivo amyloid-{beta} and tau burden was associated with the segregation and integration of brain functional connections, and episodic memory, in cognitively-unimpaired Presenilin-1 E280A carriers who are expected to develop early-onset AD dementia in approximately 13 years on average. Compared to non-carriers, mutation carriers exhibited less functional segregation and integration in posterior default-mode network (DMN) regions, particularly the precuneus, and in the retrospenial cortex, which has been shown to link medial temporal regions and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus. Greater tau burden was associated with lower segregated and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was related to higher segregated and integrated functional connectivity in the retrospenial cortex, and the anterior cingulate cortex, a hub of the salience network. These findings enlighten our understanding of how AD-related pathology distinctly alters the brains functional architecture in the preclinical stage, possibly contributing to pathology propagation and ultimately resulting in dementia. SIGNIFICANCE STATEMENTAmyloid-{beta} and tau pathologies in Alzheimers disease (AD) are hypothesized to propagate through functional networks. Research is needed to elucidate how AD-related pathologies alter the brains functional connections years before symptom-onset to help predict pathology accumulation and dementia risk. Using high-resolution (voxel-level) graph-based network analyses and PET imaging, we showed that greater tau burden was associated with largely dysconnectivity of posterior default-mode network brain regions, and increased connectivity of structures associated with the salience network and others that are critical for integrating information across neural systems in cognitively-unimpaired Presenilin-1 E280A carriers. Findings enlighten how amyloid-{beta} and tau relate to distinct patterns of functional connectivity in regions that underlie memory functioning and are critical for information processing, helping predict disease progression.

neuroscience↗

bioRxiv2019

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimers disease reveal intraneuronal Abeta42 accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic implications

Alzheimers disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies. Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intra- and extracellular A{beta}42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation are a valid model of AD and provide important clues for the identification of targetable pathological molecules.

neuroscience↗