A5006946812- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- Neurological Disease Mechanisms and Treatments
- Complement system in diseases
- Computational Drug Discovery Methods
- Barrier Structure and Function Studies
- Inflammation biomarkers and pathways
- Microtubule and mitosis dynamics
- Mitochondrial Function and Pathology
- Neurogenesis and neuroplasticity mechanisms
- Tryptophan and brain disorders
- S100 Proteins and Annexins
- Neuropeptides and Animal Physiology
- 14-3-3 protein interactions
- Receptor Mechanisms and Signaling
- Sphingolipid Metabolism and Signaling
- Nanoplatforms for cancer theranostics
- Retinal Development and Disorders
- Mast cells and histamine
- Medicinal Plants and Neuroprotection
- Advanced Neuroimaging Techniques and Applications
- Cholinesterase and Neurodegenerative Diseases
- Piperaceae Chemical and Biological Studies
- Medicinal Plants and Bioactive Compounds
University of California, Irvine
2021-2025
Irvine University
2023
Biomedical Research Networking Center on Neurodegenerative Diseases
2014-2021
Universidad de Málaga
2014-2021
Instituto de Investigación Biomédica de Málaga
2014-2021
Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation of components intermediate filaments, is common feature in brains Alzheimer's patients. astrocytes are found close association with neuritic plaques; however, the precise role these glial cells disease pathogenesis unknown. In this study, using immunohistochemical techniques light electron microscopy, we report that plaque-associated reactive enwrap, engulf may digest presynaptic dystrophies...
Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, complex disorders such as Alzheimer's (AD), the generation availability innumerous distinct animal present unique challenges to AD researchers hinder success useful therapies. Here, we conducted an in-depth analysis 3xTg-AD mouse model across its lifespan better inform field various pathologies that appear at specific ages, comment on drift has occurred in...
Abstract Background The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer’s Disease (AD). Unfortunately, many current Trem2 mouse models are associated with cryptic mRNA splicing mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed NSS ( N ormal S plice ite) model which expressed at similar level to wild-type without evidence products. Methods mice were treated demyelinating agent cuprizone, or...
Abstract Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid‐β plaques in Alzheimer's disease (AD). We have previously shown that reactive enwrap, phagocytose, degrade synapses the hippocampus of APP mice AD patients, but affecting less than 7% suggesting reduced phagocytic capacity AD. Here, we aimed to gain insight into underlying mechanisms by analyzing primary astrocyte cultures phagocytose isolated (synaptoneurosomes, SNs) from...
Neuronal loss is the best neuropathological substrate that correlates with cortical atrophy and dementia in Alzheimer's disease (AD). Defective GABAergic neuronal functions may lead to network hyperactivity aberrant oscillations consequence, generate a detrimental alteration memory processes. In this study, using immunohistochemical stereological approaches, we report two major non-overlapping groups of inhibitory interneurons (SOM-cells PV-cells) displayed distinct vulnerability perirhinal...
Abstract Multiple studies have recognized the involvement of complement cascade during Alzheimer’s disease pathogenesis. However, specific role C5a-C5aR1 signaling in progression this neurodegenerative is still not clear. Furthermore, its potential as a therapeutic target to treat AD remains be elucidated. Canonically, generation anaphylatoxin C5a result activation and interaction with receptor C5aR1 triggers potent inflammatory response. Previously, genetic ablation mouse model exerted...
The complement system is part of the innate immune that clears pathogens and cellular debris. In healthy brain, influences neurodevelopment neurogenesis, synaptic pruning, clearance neuronal blebs, recruitment phagocytes, protects from pathogens. However, excessive downstream activation leads to generation C5a, C5a engagement with its receptor C5aR1, instigates a feed-forward loop inflammation, injury, death, making C5aR1 potential therapeutic target for neuroinflammatory disorders. ablation...
The progressive cognitive decline leading to dementia in Alzheimer's disease (AD) patients is the consequence of a severe loss synapses and neurons affecting particular cell subpopulations selected brain areas, with subiculum being one t
Abstract In Alzheimer’s disease (AD), and other tauopathies, microtubule destabilization compromises axonal synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, effect stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated impact brain-penetrant microtubule-stabilizing...
Abstract BACKGROUND Variants in ABCA7 , a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS CRISPR‐Cas9 was used to generate an Abca7 V1613M variant mice, modeling homologous human V1599M variant, and extensive characterization performed. RESULTS microglia show differential gene expression profiles upon lipopolysaccharide challenge phagocytic capacity. Homozygous mice display elevated circulating...
Abstract INTRODUCTION Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play significant role in risk and resilience. However, the of diversity preclinical AD studies has received limited attention. METHODS We crossed five Collaborative Cross strains 5xFAD C57BL/6J female mice to generate F1 without transgene. Amyloid plaque pathology, microglial astrocytic responses, neurofilament light chain levels, gene expression were...
Alzheimer's disease (AD) is the leading cause of dementia in older adults, and need for effective, sustainable therapeutic targets imperative. The complement pathway has been proposed as a target. C5aR1 inhibition reduces plaque load, gliosis, memory deficits animal models, however, cellular bases underlying this neuroprotection were unclear. Here, we show that antagonist PMX205 improves outcomes Arctic48 mouse model AD. A combination single cell nucleus RNA-seq analysis hippocampi derived...
Galectin-3 (Gal3) is a regulator of microglial activation implicated in Alzheimer's disease (AD). However, Gal3 role modulating phenotype towards amyloid-beta (Aβ) remains poorly understood. We demonstrate that affects several functions and binds Aβ fibrils with high affinity, stabilizing aggregation intermediates alter fibril kinetics morphology. Furthermore, deletion the direct relationship between microglia Aβ, reducing its uptake increasing compaction. AlphaFold modeling predicts...
Alzheimer's disease is a major neurodegenerative disorder that leads to severe cognitive deficits in the elderly population. Over past two decades, multiple studies have focused on elucidating causative factors underlying memory defects patients. In this regard, new evidence linking disease-related pathology and neuronal stem cells suggests hippocampal neurogenesis impairment an important factor these deficits. However, because of conflicting results, impact Aβ neurogenesis/gliogenesis...
Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated this excessive synapses AD. Here, we investigated the effect C5aR1 inhibition on microglial and astroglial two mouse models
Abstract INTRODUCTION The BIN1 coding variant rs138047593 (K358R) is linked to Late‐Onset Alzheimer's Disease (LOAD) via targeted exome sequencing. METHODS To elucidate the functional consequences of this rare on brain amyloidosis and neuroinflammation, we generated K358R knock‐in mice using CRISPR/Cas9 technology. These were subsequently bred with 5xFAD transgenic mice, which serve as a model for pathology. RESULTS presence leads increased cerebral amyloid deposition, dampened response...
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features best correlate with typical early cognitive decline in disease. At histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along accumulation of amyloid-beta (Abeta) peptides form extracellular deposits....
Significance As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses, chronic inflammation mediated receptors represents a key mechanism which amyloid-beta (Aβ) drives development of cognitive decline in Alzheimer’s disease (AD). A crucial aspect this process failure to resolve inflammation, involves suppression cell influx endocytosis receptors. We found that ablation endosomal adaptor target Myb1 (TOM1) worsens neuroinflammation,...
Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance autosomal dominant Disease (AD). However, it remains unclear whether and how this exerts its protective effects.
Alzheimer's disease (AD) is the leading cause of dementia in older adults, and need for effective, sustainable therapeutic targets imperative. Pharmacologic inhibition C5aR1 reduces plaque load, gliosis memory deficits animal models. However, cellular basis underlying this neuroprotection which processes were consequence amyloid reduction vs alteration response to unclear. In Arctic model, antagonist PMX205 did not reduce but short-term female mice prevented. Hippocampal single cell nucleus...