Relationship between microtubule-binding repeats and morphology of neurofibrillary tangle in Alzheimer's disease

Abstract The molecular biological mechanisms of Alzheimer’s disease (AD) involve disease-associated crosstalk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available as well as our own gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were increased specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

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Alzheimer’s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort

Journal of Alzheimer s Disease ◽

10.3233/jad-210059 ◽

2021 ◽

pp. 1-10

Author(s):

Douglas Barthold ◽

Laura E. Gibbons ◽

Zachary A. Marcum ◽

Shelly L. Gray ◽

C. Dirk Keene ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Education ◽

Descriptive Analysis ◽

Neurofibrillary Tangle ◽

Apoe Genotype ◽

Severity Index ◽

Neuritic Plaque ◽

Braak Stage ◽

Total N

Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1–42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1–42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

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“End-Stage” Neurofibrillary Tangle Pathology in Preclinical Alzheimer's Disease: Fact or Fiction?

Journal of Alzheimer s Disease ◽

10.3233/jad-2011-101980 ◽

2011 ◽

Vol 25 (3) ◽

pp. 445-453 ◽

Cited By ~ 26

Author(s):

Erin L. Abner ◽

Richard J. Kryscio ◽

Frederick A. Schmitt ◽

Karen S. SantaCruz ◽

Gregory A. Jicha ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangle ◽

Preclinical Alzheimer’S Disease ◽

Tangle Pathology ◽

End Stage

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Phosphorylation, Microtubule Binding and Aggregation of Tau Protein in Alzheimer's Disease

Alzheimer's Disease ◽

10.1002/0470846453.ch55 ◽

2003 ◽

pp. 601-607

Author(s):

Jesús Ávila ◽

José J. Lucas ◽

Filip Lim ◽

Mar Pérez ◽

Félix Hernández ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Microtubule Binding

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Smuggle tau through a secret(ory) pathway

Biochemical Journal ◽

10.1042/bcj20210324 ◽

2021 ◽

Vol 478 (14) ◽

pp. 2921-2925

Author(s):

Hao Xu (徐昊)

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Recent Work ◽

Molecular Mechanisms ◽

Binding Protein ◽

Nerve Cells ◽

Transmembrane Domains ◽

Tau Pathology ◽

Microtubule Binding

Secretion of misfolded tau, a microtubule-binding protein enriched in nerve cells, is linked to the progression of tau pathology. However, the molecular mechanisms underlying tau secretion are poorly understood. Recent work by Lee et al. [Biochemical J. (2021) 478: 1471–1484] demonstrated that the transmembrane domains of syntaxin6 and syntaxin8 could be exploited for tau release, setting a stage for testing a novel hypothesis that has profound implications in tauopathies (e.g. Alzheimer's disease, FTDP-17, and CBD/PSP) and other related neurodegenerative diseases. The present commentary highlights the importance and limitations of the study, and discusses opportunities and directions for future investigations.

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Air Pollution, Combustion and Friction Derived Nanoparticles, and Alzheimer’s Disease in Urban Children and Young Adults

Advances in Alzheimer’s Disease - Alzheimer’s Disease and Air Pollution ◽

10.3233/aiad210008 ◽

2021 ◽

Author(s):

Lilian Calderón-Garcidueñas ◽

Angélica González-Maciel ◽

Randy J. Kulesza ◽

Luis Oscar González-González ◽

Rafael Reynoso-Robles ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Air Pollution ◽

Young Adults ◽

Particulate Matter ◽

Mexico City ◽

Neurofibrillary Tangle ◽

Rapid Progression ◽

Us Epa ◽

Children And Young Adults

Exposures to fine particulate matter (PM2.5) and ozone (O3)≥US EPA standards are associated with Alzheimer’s disease (AD) risk. The projection of 13.8 million AD cases in the US by the year 2050 obligate us to explore early environmental exposures as contributors to AD risk and pathogenesis. Metropolitan Mexico City children and young adults have lifetime exposures to PM2.5 and O3, and AD starting in the brainstem and olfactory bulb is relentlessly progressing in the first two decades of life. Magnetite combustion and friction-derived nanoparticles reach the brain and are associated with early and progressive damage to the neurovascular unit and to brain cells. In this review: 1) we highlight the interplay environment/genetics in the AD development in young populations; 2) comment upon ApoE ε4 and the rapid progression of neurofibrillary tangle stages and higher suicide risk in youth; and 3) discuss the role of combustion-derived nanoparticles and brain damage. A key aspect of this review is to show the reader that air pollution is complex and that profiles change from city to city with common denominators across countries. We explore and compare particulate matter profiles in Mexico City, Paris, and Santiago in Chile and make the point of why we should invest in decreasing PM2.5 to at least our current US EPA standard. Multidisciplinary intervention strategies are critical for prevention or amelioration of cognitive deficits and AD progression and risk of suicide in young individuals. AD pathology evolving from childhood is threating the wellbeing of future generations.

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Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age

Brain ◽

10.1093/brain/awz378 ◽

2019 ◽

Vol 143 (1) ◽

pp. 320-335 ◽

Cited By ~ 15

Author(s):

Tobey J Betthauser ◽

Rebecca L Koscik ◽

Erin M Jonaitis ◽

Samantha L Allison ◽

Karly A Cody ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Middle Age ◽

Neurofibrillary Tangle ◽

Imaging Biomarkers ◽

Cognitive Tests ◽

Preclinical Alzheimer’S Disease ◽

Significant Group ◽

Health Factors

Abstract This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer’s Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I–VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer’s disease during late middle-age. Within the Alzheimer’s disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer’s disease.

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A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer’s Disease

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2019.00310 ◽

2019 ◽

Vol 12 ◽

Author(s):

Samuel Kakraba ◽

Srinivas Ayyadevara ◽

Narsimha Reddy Penthala ◽

Meenakshisundaram Balasubramaniam ◽

Akshatha Ganne ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Protein Aggregation ◽

Microtubule Binding

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Aluminum Neurotoxicity — Potential Role in the Pathogenesis of Neurofibrillary Tangle Formation

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100037082 ◽

1986 ◽

Vol 13 (S4) ◽

pp. 441-445 ◽

Cited By ~ 30

Author(s):

Daniel P. Perl ◽

William W. Pendlebury

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangle ◽

Bulk Analysis ◽

Ongoing Research ◽

Aluminum Salts ◽

Neuronal Populations ◽

Large Numbers ◽

Aluminum Neurotoxicity

Abstract:Alzheimer's disease is a progressive neurodegenerative disease characterized neuropathologically by the development of large numbers of neurofibrillary tangles in certain neuronal populations of affected brains. This paper presents a review of the available evidence which suggests that aluminum is associated with Alzheimer's disease and specifically with the development of the neurofibrillary tangle. Aluminum salts innoculated into experimental animals produce neurofilamentous lesions which are similar, though not identical, to the neurofibrillary tangle of man. Although a few reports have suggested evidence of increased amounts of aluminum in the brains of Alzheimer's disease victims, such bulk analysis studies have been difficult to replicate. Using scanning electron microscopy with x-ray spectrometry, we have identified accumulations of aluminum in neurofibrillary tangle-bearing neurons of Alzheimer's disease. Similar accumulations have been identified in the neurofibrillary tangle-bearing neurons found in the brains of indigenous natives of Guam who suffer from parkinsonism with dementia and amyotrophic lateral sclerosis. This ongoing research still cannot ascribe a causal role of aluminum in the pathogenesis of neurofibrillary tangle formation; however, it does suggest that environmental factors may play an important part in the formation of this abnormality.

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Neuron loss associated with age but not Alzheimer's disease pathology in the chimpanzee brain

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0619 ◽

2020 ◽

Vol 375 (1811) ◽

pp. 20190619 ◽

Cited By ~ 3

Author(s):

Melissa K. Edler ◽

Emily L. Munger ◽

Richard S. Meindl ◽

William D. Hopkins ◽

John J. Ely ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangle ◽

Cell Loss ◽

Tau Proteins ◽

Middle Temporal Gyrus ◽

Neuron Death ◽

Neuron Loss ◽

Neuron Density ◽

Age Related

In the absence of disease, ageing in the human brain is accompanied by mild cognitive dysfunction, gradual volumetric atrophy, a lack of significant cell loss, moderate neuroinflammation, and an increase in the amyloid beta (A β ) and tau proteins. Conversely, pathologic age-related conditions, particularly Alzheimer's disease (AD), result in extensive neocortical and hippocampal atrophy, neuron death, substantial A β plaque and tau-associated neurofibrillary tangle pathologies, glial activation and severe cognitive decline. Humans are considered uniquely susceptible to neurodegenerative disorders, although recent studies have revealed A β and tau pathology in non-human primate brains. Here, we investigate the effect of age and AD-like pathology on cell density in a large sample of postmortem chimpanzee brains ( n = 28, ages 12–62 years). Using a stereologic, unbiased design, we quantified neuron density, glia density and glia:neuron ratio in the dorsolateral prefrontal cortex, middle temporal gyrus, and CA1 and CA3 hippocampal subfields. Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia densities. Differing from cerebral ageing and AD in humans, these data indicate that chimpanzees exhibit regional neuron loss with ageing but appear protected from the severe cell death found in AD. This article is part of the theme issue ‘Evolution of the primate ageing process’.

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