A5013535951- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Mitochondrial Function and Pathology
- Parkinson's Disease Mechanisms and Treatments
- Cholinesterase and Neurodegenerative Diseases
- Tryptophan and brain disorders
- Protein Kinase Regulation and GTPase Signaling
- Viral-associated cancers and disorders
- Herpesvirus Infections and Treatments
- Cytomegalovirus and herpesvirus research
- Nuclear Receptors and Signaling
- Functional Brain Connectivity Studies
- Neuroinflammation and Neurodegeneration Mechanisms
- Microtubule and mitosis dynamics
- RNA regulation and disease
- Autophagy in Disease and Therapy
- Advanced Neuroimaging Techniques and Applications
- Axon Guidance and Neuronal Signaling
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Neurogenetic and Muscular Disorders Research
- Cellular transport and secretion
- 14-3-3 protein interactions
- Amyotrophic Lateral Sclerosis Research
- NF-κB Signaling Pathways
- Epigenetics and DNA Methylation
University of Alabama at Birmingham
2015-2024
St. Vincent's Birmingham
2015-2023
Emory University
2005-2013
German Center for Neurodegenerative Diseases
2010-2013
Objective Neuroimaging and other biomarker assays suggest that the pathological processes of Alzheimer's disease (AD) begin years prior to clinical dementia onset. However, some 30 50% older individuals who harbor AD pathology do not become symptomatic in their lifetime. It is hypothesized such exhibit cognitive resilience protects against dementia. We cases with pathology, structural changes dendritic spines would distinguish had or did have Methods compared within layer II III pyramidal...
Alzheimer's disease (AD) is the leading cause of dementia and has no cure. Genetic, cell biological, biochemical studies suggest that reducing amyloid-β (Aβ) production may serve as a rational therapeutic avenue to delay or prevent AD progression. Inhibition RhoA, Rho GTPase family member, proposed curb Aβ production. However, barrier this hypothesis been limited understanding how principal downstream effectors Rho-associated, coiled-coil containing protein kinase (ROCK) 1 ROCK2, modulate...
Abstract Alzheimer's disease ( AD ) is the leading cause of dementia and mitigating amyloid‐β (Aβ) levels may serve as a rational therapeutic avenue to slow progression. Pharmacologic inhibition Rho‐associated protein kinases ROCK 1 2) proposed curb Aβ levels, mechanisms that underlie 2′s effects on production are defined. How affects generation remains critical barrier. Here, we report were elevated in mild cognitive impairment due (MCI) brains compared controls. Aβ42 oligomers marginally...
The molecular mechanisms and pathways enabling certain individuals to remain cognitively normal despite high levels of Alzheimer's disease (AD) pathology incompletely understood. These people with AD are described as preclinical or asymptomatic (AsymAD) appear exhibit cognitive resilience the clinical manifestations dementia. Here we present a comprehensive network-based approach from cases clinically pathologically defined map resilience-associated extend mechanistic validation. Multiplex...
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative four-repeat tauopathies with no cure. Mitigating pathogenic tau levels is a rational strategy for tauopathy treatment, but therapeutic targets clinically available drugs lacking. Here, we report that protein of the Rho-associated kinases (ROCK1 ROCK2), p70 S6 kinase (S6K), mammalian target rapamycin (mTOR) were increased in PSP CBD brains. RNAi depletion ROCK1 or ROCK2 reduced mRNA level human...
Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson's Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, up to 80% PD patients develop dementia. α-Syn are abundant in the hippocampus, yet functional consequences unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous form resembling those found diseased brains by treating hippocampal neurons fibrils. At seven days after adding fibrils, axons, but there...
Communication among neurons is mediated through synaptic connections between axons and dendrites, most excitatory synapses occur on actin-rich protrusions along dendrites called dendritic spines. Dendritic spines are structurally dynamic, synapse strength closely correlated with spine morphology. Abnormalities in the size, shape, number of prevalent neurologic diseases, including autism spectrum disorders, schizophrenia, Alzheimer disease. However, therapeutic targets that influence...
Alzheimer's disease (AD) therapies predominantly focus on β-amyloid (Aβ), but Aβ effects may be maximal before clinical symptoms appear. Downstream of Aβ, dendritic spine loss correlates most strongly with cognitive decline in AD. Rho-associated kinases (ROCK1 and ROCK2) regulate the actin cytoskeleton, ROCK1 ROCK2 protein abundances are increased early Here, we found that abundance cultured primary rat hippocampal neurons reduced length through a myosin-based pathway, whereas induced serine...
Abstract Brain‐derived neurotrophic factor ( Bdnf ) plays a critical role in brain development, dendritic growth, synaptic plasticity, as well learning and memory. The rodent gene contains nine 5′ non‐coding exons I – IXa ), which are spliced to common 3′ coding exon IX ). Transcription of individual variants, all encode the same BDNF protein, is initiated at unique promoters upstream each exon, enabling precise spatiotemporal activity‐dependent regulation expression. Although prior evidence...
Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease characterized by behavioral abnormalities, personality changes, language dysfunction, and can co-occur with the development of motor neuron disease. One major pathological form FTLD intracellular deposition ubiquitinated phosphorylated TAR DNA binding protein-43 (TDP-43), suggesting that dysregulation in phosphorylation events may contribute to progression. However, date systematic analysis phosphoproteome...
A hallmark of neurodegeneration is the aggregation disease related proteins that are resistant to detergent extraction. In major pathological subtype frontotemporal lobar degeneration (FTLD), modified TAR-DNA binding protein 43 (TDP-43), including phosphorylated, ubiquitinated, and proteolytically cleaved forms, enriched in detergent-insoluble fractions from post-mortem brain tissue. Additional accumulate FTLD proteome remain largely unknown. this study, we used stable isotope-labeled...
TAR DNA-binding protein 43 (TDP-43) is a nuclear involved in RNA splicing and major component ubiquitin-positive, tau-negative inclusions of frontotemporal lobar degeneration amyotrophic lateral sclerosis. Under disease conditions, TDP-43 redistributes to the cytoplasm where it can be phosphorylated, ubiquitinated, proteolytically cleaved. Enzymes responsible for proteolytic processing brain remain largely unreported. Using MS approach, we identified two truncated peptides, terminating...
Rho-associated coiled-coil containing kinase isoform 2 (ROCK2) is a member of the AGC family serine/threonine kinases and an extensively studied regulator actin-mediated cytoskeleton contractility. Over past decade, new evidence has emerged that suggests ROCK2 regulates autophagy. Recent studies indicate dysregulation autophagy contributes to development misfolded tau aggregates among entorhinal cortex (EC) excitatory neurons in early Alzheimer’s disease (AD). While accumulation oligomers...
Murine gammaherpesvirus 68 (MHV68) establishes long-term latency in memory B cells similar to the human Epstein Barr Virus (EBV). EBV encodes an interleukin-10 (IL-10) homolog and modulates cellular IL-10 expression; however, role of establishment and/or maintenance chronic infection remains unclear. Notably, MHV68 does not encode homolog, but virus has been shown result elevated serum levels wild-type mice, deficiency results decreased latency. Here we show that a unique latency-associated...
Proteolytic processing of the amyloid-β precursor protein (APP) and generation peptide (Aβ) are key events in Alzheimer's disease (AD) pathogenesis. Cell biological genetic evidence has implicated low-density lipoprotein sorting receptor LR11/SorLA AD through mechanisms related to APP Aβ production. Defining cellular pathway(s) by which LR11 modulates production is critical understanding how changes expression affect development pathology progression. We report that ectodomain required for...
Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate translational relevance this finding, longitudinal measures from human patients, RNA expression post-mortem brain tissue, data genome-wide association study (GWAS) Alzheimer's (AD),...
Murine gammaherpesvirus 68 (gammaHV68) infection of mice provides a tractable small-animal model system for assessing the requirements establishment and maintenance latency within lymphoid compartment. The M2 gene product gammaHV68 is latency-associated antigen with no discernible homology to any known proteins. Here we focus on requirement in splenic B-cell latency. Our analyses showed following. (i) Low-dose (100 PFU) inoculation administered via intranasal route resulted failure establish...
Proteomic studies utilizing postmortem human brain tissue samples have yielded robust assessments of the aging and neurodegenerative disease(s) proteomes. While these analyses provide lists molecular alterations in conditions, like Alzheimer’s disease (AD), identifying individual proteins that affect biological processes remains a challenge. To complicate matters, protein targets may be highly understudied limited information on their function. address hurdles, we sought to establish...
Brain connectivity arises from interactions across biophysical scales, ranging molecular to cellular anatomical network level. To date, there has been little progress toward integrated analysis these scales. bridge this gap, a unique cohort of 98 individuals, we collected antemortem neuroimaging and genetic data, as well postmortem dendritic spine morphometric, proteomic gene expression data the superior frontal inferior temporal gyri. Through integration morphology identified hundreds...