A5034908340- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- Mitochondrial Function and Pathology
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Dementia and Cognitive Impairment Research
- Neuroscience and Neural Engineering
- Nuclear Receptors and Signaling
- Machine Learning in Bioinformatics
- Prion Diseases and Protein Misfolding
- Neurological Disease Mechanisms and Treatments
- S100 Proteins and Annexins
- Parkinson's Disease Mechanisms and Treatments
- Functional Brain Connectivity Studies
- Cellular transport and secretion
- Advanced MRI Techniques and Applications
- Medication Adherence and Compliance
- PI3K/AKT/mTOR signaling in cancer
- Medicinal Plants and Bioactive Compounds
- Microbial infections and disease research
- Diabetes Treatment and Management
- IL-33, ST2, and ILC Pathways
- Biochemical and Structural Characterization
- Barrier Structure and Function Studies
Harvard University
2018-2024
Massachusetts General Hospital
2018-2024
University of Edinburgh
2015-2024
Harvard NeuroDiscovery Center
2021-2024
UK Dementia Research Institute
2017-2024
Universidade Estadual de Campinas (UNICAMP)
2024
Meyer Children's Hospital
2024
Malaghan Institute of Medical Research
2024
University of Florence
2024
Brazilian Institute of Neuroscience and Neurotechnology
2024
Abstract Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimer’s disease. Under pathological conditions, dissociates from axonal microtubules and missorts to pre- postsynaptic terminals. Patients suffer early synaptic dysfunction prior aggregate formation, but the underlying mechanism unclear. Here we show that pathogenic binds vesicles via its N-terminal domain interferes with presynaptic functions, vesicle mobility release rate, lowering neurotransmission fly...
A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack understanding how amyloid beta (Aβ) peptide and pathological forms tau protein cooperate in causing phenotypes. Within a mouse tau-deficient background, we probed molecular, cellular, behavioral disruption triggered by influence wild-type human on Aβ-induced pathology. We find that Aβ work cooperatively to cause hyperactivity phenotype downregulation transcription genes involved...
Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, have a later age of onset, milder clinical course, less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with major genetic risk factor for ε4, which has an onset several decades earlier, more aggressive course findings, in terms amount amyloid deposition. Here, we demonstrate brain...
Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced explain relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, β-protein (Aβ), self-associates form soluble aggregates impair synaptic network activity. Here, we used most disease-relevant Aβ, isolated from AD brain. Using this material, show synaptotoxic effects Aβ depend on expression APP Aβ-mediated impairment plasticity...
Abstract Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, periphery largely liver. ApoE has been shown to impact integrity of blood–brain barrier, and, humans, APOE4 allele gene reported lead leaky barrier. We used specific knock-in mice expressing each common (human) alleles, longitudinal multiphoton intravital microscopy, directly monitor various isoforms on barrier integrity. found that humanized APOE4, but not APOE2 or APOE3,...
Human-to-human transmission of Creutzfeldt-Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One the commonest causes iCJD was use human pituitary-derived growth hormone (hGH) to treat primary or secondary deficiency. As part a comprehensive tissue-based analysis largest cohort yet collected (35 cases) UK hGH-iCJD cases, we describe clinicopathological phenotype UK. In 33/35 cases with sufficient paraffin-embedded tissue for full pathological...
Abstract Alzheimer's disease is characterized by the presence of aggregates amyloid beta (Aβ) in senile plaques and tau neurofibrillary tangles, as well marked neuron synapse loss. Of these pathological changes, loss correlates most strongly with cognitive decline. Synapse occurs prominently around due to accumulations oligomeric Aβ. Recent evidence suggests that may also play a role but interactions Aβ remain be determined. In this study, we generated novel transgenic mouse line, APP / PS...
Abstract Degeneration of synapses in Alzheimer’s disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to pathophysiology. We recently observed that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 ( APOE 4), is associated exacerbated synapse loss accumulation oligomeric amyloid beta human AD brain. To begin understand molecular cascades involved how this mediated by , generate a resource knowledge changes proteome we...
Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with ε4 allele increasing in a dose-dependent fashion. In addition to ApoE4 playing crucial role amyloid-β deposition, recent evidence suggests that it also plays an important tau pathology and tau-mediated neurodegeneration. It not known, however, whether therapeutic reduction of would exert protective effects on neurodegeneration.Herein, we used antisense oligonucleotides (ASOs)...
Abstract Synapse loss correlates with cognitive decline in Alzheimer’s disease, and soluble oligomeric amyloid beta (Aβ) is implicated synaptic dysfunction loss. An important knowledge gap the lack of understanding how Aβ leads to synapse degeneration. In particular, there has been difficulty determining whether a receptor that binds mediates toxicity. While many candidates have observed model systems, their relevance human AD brain remains unknown. This part due methodological limitations...
To cause disease and persist in a host, pathogenic commensal microbes must adhere to tissues. Colonization infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. date, adhesins are only known bind host receptors non-covalently. Here we show streptococcal protein SfbI mediates covalent interaction with fibrinogen using an unusual internal thioester bond as ‘chemical harpoon’. This cross-linking reaction allows...
One of the major challenges in developing effective therapeutic strategies for Alzheimer's disease is understanding how genetic risk factors contribute to neurodegeneration. The apolipoprotein epsilon 4 isoform (
Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families society as a whole.Understanding the differential in brain function is critical not only for development oftherapeutics to prolong health into old age, but also gain insight pathological ageing suchas Alzheimer's disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises rare group people forwhom there are childhood test scores...
To describe temporal and spatial patterns of the prevalence pneumonia in lambs three regions New Zealand, determine effects on liveweight gain.A longitudinal study was conducted 1999- 2000 14 commercial sheep farms, five from Southland region South Island, King Country four Northland North Island. Pneumonia known to be a problem all farms selected. On each farm, 400 were randomly selected at weaning allocated random one two groups (Groups I II). Lambs both weighed 4-weekly intervals. The...
Apolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models Alzheimer’s disease (AD). Can simultaneously protect and impair neural circuits? Here, we dissociated the role AD versus aging to determine its neuronal synaptic integrity. Using two-photon calcium imaging awake mice record visually evoked responses, found that genetic removal improved responses adult APP/PSEN1...
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well astrocytes and oligodendrocytes. While astrocytic deposits are rarely observed normal aging (so-called aging-related astrogliopathy, ARTAG) Alzheimer's (AD), the form of tufted pathognomonic hallmark PSP. Classical biochemical experiments emphasized synthesis central nervous system, suggesting that inclusions might be derived from uptake extracellular neuronal-derived...
Decreased expression but increased activity of PDK1 has been observed in neurodegenerative disease. To study vivo function neuron survival during cortical development, we generate forebrain-specific conditional knockout (cKO) mice. We demonstrate that cKO mice display striking loss and apoptosis. report exhibit deficits on several behavioral tasks. Moreover, show decreased activities for Akt mTOR. These results highlight an essential role endogenous the maintenance neuronal development.
Abstract Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do have a later age of onset, milder clinical course, less severe neuropathological findings than others with disease. The contrast is especially stark in comparison to phenotype associated major genetic risk factor for ε4, which has an onset several decades earlier, as well more aggressive course notably findings, terms amount amyloid...
Abstract Synapse loss correlates with cognitive decline in Alzheimer’s disease, and soluble oligomeric amyloid beta is implicated synaptic dysfunction loss. An important knowledge gap the lack of understanding how leads to synapse degeneration. In particular, there has been difficulty determining whether a receptor that binds mediates toxicity. While many candidates have observed model systems, their relevance human AD brain remains unknown. This part due methodological limitations...