Browsing by Subject "tau"

Now showing 1 - 6 of 6
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    The Amyloid-Tau-Neuroinflammation Axis in the Context of Cerebral Amyloid Angiopathy
    (MDPI, 2019-12-14) Cisternas, Pablo; Taylor, Xavier; Lasagna-Reeves, Cristian A.; Anatomy and Cell Biology, School of Medicine
    Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with the accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis has been associated with an active immune response and perivascular deposition of hyperphosphorylated tau. Despite the fact that in Alzheimer’s disease (AD) a major focus of research has been the understanding of the connection between parenchymal amyloid plaques, tau aggregates in the form of neurofibrillary tangles (NFTs), and immune activation, the contribution of tau and neuroinflammation to neurodegeneration associated with CAA remains understudied. In this review, we discussed the existing evidence regarding the amyloid diversity in CAA and its relation to tau pathology and immune response, as well as the possible contribution of molecular and cellular mechanisms, previously associated with parenchymal amyloid in AD and AD-related dementias, to the pathogenesis of CAA. The detailed understanding of the “amyloid-tau-neuroinflammation” axis in the context of CAA could open the opportunity to develop therapeutic interventions for dementias associated with CAA that are currently being proposed for AD and AD-related dementias.
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    BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease
    (Oxford, 2016-10) Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos; Goate, Alison; Fagan, Anne M.; Benzinger, Tammie L. S.; Maruff, Paul; Snyder, Peter J.; Masters, Colin L.; Allegri, Ricardo; Chhatwal, Jasmeer; Farlow, Martin R.; Graff-Radford, Neill R.; Laske, Christoph; Levin, Johannes; McDade, Eric; Ringman, John M.; Rossor, Martin N.; Salloway, Stephen; Schofield, Peter R.; Holtzman, David M.; Morris, John C.; Bateman, Randall J.; Department of Neurology, IU School of Medicine
    The brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer’s disease. However, the effect of BDNF in autosomal dominant Alzheimer’s disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer’s disease. We explored effects of apolipoprotein E ( APOE ) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer’s disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer’s disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer’s disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer’s disease.
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    Elevated Cerebrospinal Fluid Tau Protein Concentrations on Admission Are Associated With Long-term Neurologic and Cognitive Impairment in Ugandan Children With Cerebral Malaria
    (Oxford, 2020-03-15) Datta, Dibyadyuti; Conroy, Andrea L; Castelluccio, Peter F; Ssenkusu, John M; Park, Gregory S; Opoka, Robert O; Bangirana, Paul; Idro, Richard; Saykin, Andrew J; John, Chandy C; Pediatrics, School of Medicine
    Background Elevated concentrations of cerebrospinal fluid (CSF) tau, a marker of axonal injury, have been associated with coma in severe malaria (cerebral malaria [CM]). However, it is unknown whether axonal injury is related to long-term neurologic deficits and cognitive impairment in children with CM. Methods Admission CSF tau concentrations were measured in 145 Ugandan children with CM and compared to clinical and laboratory factors and acute and chronic neurologic and cognitive outcomes. Results Elevated CSF tau concentrations were associated with younger age, increased disease severity (lower glucose and hemoglobin concentrations, malaria retinopathy, acute kidney injury, and prolonged coma duration, all P < .05), and an increased CSF:plasma albumin ratio, a marker of blood–brain barrier breakdown (P < .001). Admission CSF tau concentrations were associated with the presence of neurologic deficits at hospital discharge, and at 6, 12, and 24 months postdischarge (all P ≤ .02). After adjustment for potential confounding factors, elevated log10-transformed CSF tau concentrations correlated with worse cognitive outcome z scores over 2-year follow-up for associative memory (β coefficient, –0.31 [95% confidence interval [CI], –.53 to –.10]) in children <5 years of age, and for overall cognition (–0.69 [95% CI, –1.19 to –.21]), attention (–0.78 [95% CI, –1.34 to –.23]), and working memory (–1.0 [95% CI, –1.68 to –.31]) in children ≥5 years of age (all P < .006). Conclusions Acute axonal injury in children with CM is associated with long-term neurologic deficits and cognitive impairment. CSF tau concentrations at the time of the CM episode may identify children at high risk of long-term neurocognitive impairment.
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    Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging
    (Wiley, 2015-02) Ghetti, B.; Oblak, A. L.; Boeve, B. F.; Johnson, K. A.; Dickerson, B. C.; Goedert, M.; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Hereditary frontotemporal dementia associated with mutations in the microtubule-associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms.
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    MicroRNA Regulation of Key Proteins Involved in Alzheimer's Disease Pathogenesis
    (2022-06) Wang, Ruizhi; Du, Yansheng; Lahiri, Debomoy K.; Kim, Jungsu; Reeves, Cristian A. Lasagna; Zhou, Feng C.
    Alzheimer’s disease (AD) is a neurodegenerative disease histopathologically characterized by the coexistence of amyloid plaques and neurofibrillary tangles, mainly consisting of amyloid β peptides hyperphosphorylated tau proteins, respectively. Multiple proteins and pathways are involved in the pathogenesis of AD, including Aβ precursor protein (APP), β-site APP-cleaving enzyme (BACE1), neprilysin, endothelin converting enzyme (ECE), repressor element-1 silencing transcription factor (REST), microtubule-associated protein tau, glycogen synthase kinase, and pro-inflammatory cytokines. However, how these proteins and pathways are dysregulated and converge in AD pathogenesis remains unclear. Genetic, epigenetic and environmental factors play important roles in disease progression. MicroRNAs (miRNAs), a group of small noncoding RNAs, are important epigenetic regulators that participate in AD development. We have identified three miRNAs capable of targeting several proteins in different AD-related pathways: miR-181-5p, miR-153-3p and miR-101-3p. We tested miR-181 activity with recombinant reporter gene- MME 3’-UTR constructs. All four miR-181-5p (miR-181a, miR-181b, miR-181c and miR-181d) sequences downregulated the reporter signal. Human differentiated neural cells were transfected with miR-181d-5p mimics. miR-181d-5p treatment significantly reduced MME mRNA levels, protein levels and enzyme activity. In addition, miR-181d-5p increased tau and phosphorylated tau levels proportionally. We further demonstrate that miR-153-3p reduced REST 3’-UTR activities, mRNA and protein levels in multiple human cell lines. Moreover, we show that miR-153-3p, by knocking down REST protein, induces apoptosis in HeLa cells but not differentiated neural cells. In addition, miR-153-3p regulates neuronal differentiation in neuronal stem cells, potentially via REST knockdown. We further found that miR-153 levels were correlated with a reduced likelihood of developing AD. Last, we demonstrated that miR-101-3p reduced ECE1 and GSK3β protein levels in multiple cell lines. miR-101-3p increased REST and pro-inflammatory cytokine secretion in microglia cells. In sum, we tested the hypothesis that miRNAs can serve as the master regulator of AD pathogenesis.
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    Tau and neurodegeneration : neuroimaging, genes, and biomarkers
    (2017-06-29) Deters, Kacie Danielle; Vidal, Ruben; Risacher, Shannon L.; Saykin, Andrew J.; Farlow, Martin; Nho, Kwangsik; Gao, Sujuan
    The pathway leading from soluble and monomeric to hyperphosphorylated, insoluble and filamentous tau protein is at the center of many human neurodegenerative diseases, collectively referred to as tauopathies, such as Alzheimer disease (AD). In this report, we discuss the role of neuroimaging, genetics, and biomarkers in better understanding the underlying brain changes in tauopathies. In Chapters 1 and 2, we review current knowledge of tauopathies, the protein tau and FDG PET studies in AD. In Chapter 3, we investigate glucose metabolism using [18F]FDG PET in a family with multiple systems tauopathy with presenile dementia (MSTD), a primary tauopathy cause by a mutation in MAPT. The results from this study suggest that mutation carriers have lower [18F]FDG uptake, which may precede clinical onset. In Chapter 4, we assessed brain glucose metabolism using [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) in individuals with Gerstmann–Sträussler–Scheinker Disease (GSS) with the PRNP F198S mutation. The results from this study suggest hypometabolism in the cerebellar and striatal regions, which may be preceded by hypermetabolism. This chapter also evaluated if [11C]Pittsburgh Compound B (PiB) PET is capable of detecting PrP-amyloid in GSS in individuals with the PRNP P102L and F198S mutations. The results from this study suggest that [11C]PiB is not suitable for in vivo assessment of PrP amyloid plaques in GSS. In Chapter 5, we examine a correlation between two peripheral markers of axonal degeneration, plasma tau and neurofilament light (NFL), and MRI. The results from this study suggest that plasma NFL may be a more specific marker for neurodegeneration relative to plasma tau. In Chapter 6, we attempted to create a tau biological network from gene and protein databases and literature search. We identified over 150 genes that are related to tau protein or MAPT that are involved in different biological functions. Overall, the results of this report support the notion that using a combination of techniques may help model progression of tau pathology. Future studies may establish additional markers that may be used in combination with some of these measures as tools for diagnosis and for the evaluation of treatment efficacy in therapeutic trials.