A5013330262- Tryptophan and brain disorders
- Extracellular vesicles in disease
- Alzheimer's disease research and treatments
- Stress Responses and Cortisol
- Neurotransmitter Receptor Influence on Behavior
- Diet and metabolism studies
- Schizophrenia research and treatment
- Treatment of Major Depression
- Neuroinflammation and Neurodegeneration Mechanisms
- Bipolar Disorder and Treatment
- Anesthesia and Neurotoxicity Research
- Neurological Disorders and Treatments
- Resilience and Mental Health
- Electroconvulsive Therapy Studies
- Alcohol Consumption and Health Effects
- MicroRNA in disease regulation
- Attention Deficit Hyperactivity Disorder
- Parkinson's Disease Mechanisms and Treatments
- Receptor Mechanisms and Signaling
- Hormonal Regulation and Hypertension
- Traumatic Brain Injury Research
- Dietary Effects on Health
- Sleep and related disorders
- Sleep and Wakefulness Research
- Cardiac Health and Mental Health
Institute on Aging
2017-2025
National Institute on Aging
2016-2025
National Institutes of Health
2015-2025
Rudjer Boskovic Institute
2005-2014
University of California, San Diego
2013-2014
VA San Diego Healthcare System
2013
Our team has been a pioneer in harvesting extracellular vesicles (EVs) enriched for neuronal origin from peripheral blood and using them as biomarker discovery platform neurological disorders. This methodology demonstrated excellent diagnostic predictive performance Alzheimer's other neurodegenerative diseases multiple studies, providing strong proof of concept this approach. Here, we describe our detail offer further evidence that isolated EVs are origin. In addition, present represent more...
Efficient intercellular transfer of RNAs, proteins, and lipids as protected exosomal cargo has been demonstrated in the CNS, but distinct physiologic pathologic roles have not well defined for this pathway. The capacity to isolate immunochemically human plasma neuron-derived exosomes (NDEs), containing neuronspecific cargo, permitted characterization CNS-derived living humans. Constituents amyloid β-peptide (Aβ)42-generating system now are examined 2 sets neural cells by quantification...
<h3>Importance</h3> Exenatide, a glucagon-like peptide 1 agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function randomized, placebo-controlled trial Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play role PD pathogenesis; however, exploring the extent which drugs engage with putative mechnisms vivo remains challenge. <h3>Objective</h3> To assess whether participants...
Abstract Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural‐derived exosomes of Alzheimer's disease or frontotemporal dementia patients and matched controls. Exosomal levels low‐density lipoprotein receptor‐related protein 6, heat‐shock factor‐1, repressor element 1‐silencing transcription factor all significantly lower than controls ( P < 0.0001). In dementia, the only significant difference was higher diminished 2–10 years...
Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported exhibit elevated levels phosphorylated (p) tau, Aβ42, and insulin receptor substrate 1 (IRS-1).To validate nEV as predictors.This case-control study included longitudinal plasma samples from cognitively normal participants in Baltimore Longitudinal Study Aging...
Progressive cerebral accumulation of tau aggregates is a defining feature Alzheimer’s disease (AD). A popular theory that seeks to explain the apparent spread neurofibrillary tangle pathology proposes aggregated passed from neuron neuron. Such templated seeding process requires transferred contains microtubule binding repeat domains are necessary for aggregation. While it not clear how protein such as can move cell cell, previous reports have suggested this may involve extracellular vesicles...
It was recently discovered that brain cells release extracellular vesicles (EV) which can pass from into blood. These findings raise the possibility brain-derived EV's present in blood be used to monitor disease processes occurring cerebrum. Since levels of certain micro-RNAs (miRNAs) have been reported altered Alzheimer's (AD) brain, we sought assess miRNA dysregulation AD tissue and determine if these changes were reflected neural EVs isolated subjects with AD. To this end, employed...
As SARS-CoV-2 is known to invade neural cell mitochondria, a plasma system for quantifying central nervous proteins in living humans was used investigate neuropathogenic mechanisms of long-COVID-19.
Objective: Identify biomarkers in peripheral blood that relate to chronic post-concussive and behavioural symptoms following traumatic brain injuries (TBIs) ultimately improve clinical management.Research design: We compared military personnel with mild TBIs (mTBIs) (n = 42) those without 22) concentrations of tau, amyloid-beta (Aβ42) cytokines (tumour necrosis factor alpha (TNFα, interleukin (IL)-6 -10) neuronal-derived exosomes from the blood. utilized nanosight technology coupled...
Abstract Brain insulin resistance (IR), which depends on insulin‐receptor‐substrate‐1 (IRS‐1) phosphorylation, is characteristic of Alzheimer's disease (AD). Previously, we demonstrated higher pSer312‐IRS‐1 (ineffective signaling) and lower p‐panTyr‐IRS‐1 (effective in neural origin‐enriched plasma exosomes AD patients vs. controls. Here, hypothesized that these exosomal biomarkers associate with brain atrophy AD. We studied 24 subjects biomarker‐supported probable (low CSF Aβ 42 ). Exosomes...
Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer's Disease (AD).We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety tolerability of exenatide explore treatment responses clinical, cognitive, biomarker outcomes early AD.Eighteen participants with high probability AD based on cerebrospinal...
Abstract Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane that have recently been implicated prion-like spread of self-aggregating proteins. Here we report EVs isolated from AD patient cerebrospinal fluid and plasma, plasma two mouse models, medium neural cells expressing familial presenilin 1 mutations,...
Neuron-derived exosomes (NDEs) were enriched by anti-L1CAM antibody immunoabsorption from plasmas of subjects ages 18–26 yr within 1 wk after a sports-related mild traumatic brain injury (acute mTBI) (n = 18), 3 mo or longer the last 2–4 mTBIs (chronic 14) and with no recent history TBI (controls) 21). Plasma concentrations NDEs, assessed counts levels extracted exosome marker CD81, significantly depressed mean 45% in acute mTBI (P < 0.0001), but not chronic mTBI, compared controls. Mean...
Besides motor symptoms, many individuals with Parkinson's disease develop cognitive impairment perhaps due to coexisting α-synuclein and Alzheimer's pathologies impaired brain insulin signalling. Discovering biomarkers for in could help clarify the underlying pathogenic processes improve diagnosis prognosis. This study used plasma samples from 273 participants: 103 normal cognition, 121 (81 mild impairment, 40 dementia) 49 age- sex-matched controls. Plasma extracellular vesicles enriched...
Abstract Declining nicotinamide adenine dinucleotide (NAD + ) concentration in the brain during aging contributes to metabolic and cellular dysfunction is implicated pathogenesis of aging‐associated neurological disorders. Experimental therapies aimed at boosting NAD levels normalize several neurodegenerative phenotypes animal models, motivating their clinical translation. Dietary intake precursors, such as riboside (NR), a safe effective avenue for augmenting peripheral tissues humans, yet...
Abstract Isolation of neuron‐derived extracellular vesicles (NDEVs) with L1 Cell Adhesion Molecule (L1CAM)‐specific antibodies has been widely used to identify blood biomarkers CNS disorders. However, full methodological validation requires demonstration L1CAM in individual NDEVs and lower levels or absence EVs from other cells. Here, we multiple single‐EV techniques establish the neuronal origin determine abundance L1CAM‐positive human blood. epitopes ectodomain are shown be co‐expressed on...
Plasma endothelial cell–derived exosomes (EDEs) and platelet-derived (PDEs) were precipitated enriched separately by immunospecific absorption procedures for analyses of cargo proteins relevant to atherosclerosis. EDEs had usual exosome size marker protein content, significantly higher levels than PDEs the vascular cell adhesion molecule-1 (VCAM-1) nitric oxide synthase, whereas platelet glycoprotein VI. EDE VCAM-1, von Willebrand factor, growth factor (PDGF)-BB, angiopoietin-1, lysyl...
Possible involvement of complement (C) systems in the pathogenesis traumatic brain injury (TBI) was investigated by quantifying Cproteins plasma astrocyte-derived exosomes (ADEs) subjects with sports-related TBI (sTBI) and military veterans (mtTBI) without cognitive impairment. All sTBI (n = 24) had mild injuries, whereas eight mtTBI moderate, 17 injuries. Plasma levels ADEs were decreased after acute returned to normal within months. Cprotein from 12- 35-fold higher than corresponding...
Background:Insulin resistance is implicated in Alzheimer's disease (AD), whereas intranasal insulin an experimental treatment clinical trials. We previously proposed signaling mediators plasma neuronal-enriched extracellular vesicles (EVs) as biomarkers of brain resistance. Objective:We sought to demonstrate the capacity EV target engagement response and their ability track treatment-associated cognitive changes AD. Methods:We isolated EVs from samples participants with amnestic mild...
To identify long-term effects of traumatic brain injury (TBI) on levels plasma neuron-derived exosome (NDE) protein biomarkers cognitive impairment (CI), plasmas were obtained from four groups older veterans, who matched for age and sex: no TBI or CI (n = 42), with 19), without 21), 26). The was sustained 12 to 74 years before the study in 75%. NDEs enriched by sequential precipitation anti-L1CAM antibody immunoabsorption, extracted quantified enzyme-linked immunosorbent assays. Chronic NDE...