The relationship between subcortical tau pathology and Alzheimer's disease

2012 ◽  
Vol 40 (4) ◽  
pp. 711-715 ◽  
Author(s):  
Johannes Attems ◽  
Dietmar R. Thal ◽  
Kurt A. Jellinger
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Neuronal Damage ◽  
The Other ◽  
Tau Pathology ◽  
Subcortical Nuclei ◽  
Ad Alzheimer’S Disease ◽  
The Relationship ◽  
Transentorhinal Region

The stepwise progression of tau pathology [NFTs (neurofibrillary tangles) and NTs (neuropil threads)] in AD (Alzheimer's disease) is generally assumed to begin in the transentorhinal region (entorhinal stage) from which it progresses to the hippocampus (limbic stage) and to neocortical regions (neocortical stage). This stepwise progression is reflected in the NFT Braak stages. However, it has been shown recently that tau pathology is frequently seen in subcortical nuclei, in particular the LC (locus coeruleus) in over 90% of individuals under 30 years of age, suggesting that AD-associated tau pathology begins in the LC and not in the transentorhinal region. On the other hand, only minimal amounts of tau pathology are seen in the LC in cases with considerable entorhinal tau pathology, while the severity of tau pathology in the LC significantly increases with increasing NFT Braak stages. These findings suggest that the LC becomes increasingly involved during AD progression rather than representing the site initially affected. Further studies are warranted to answer the question of whether tau pathology in the LC of young individuals is associated with AD or whether it rather reflects non-specific neuronal damage.

The relationship between αB-crystallin and neurofibrillary tangles in Alzheimer's disease

2001 ◽  
Vol 27 (3) ◽  
pp. 180-188 ◽  
Author(s):  
J. J. Mao ◽  
S. Katayama ◽  
C. Watanabe ◽  
Y. Harada ◽  
K. Noda ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Αb Crystallin ◽  
The Relationship

Insights from Drosophila models of Alzheimer's disease

2010 ◽  
Vol 38 (4) ◽  
pp. 988-992 ◽  
Author(s):  
Catherine M. Cowan ◽  
David Shepherd ◽  
Amritpal Mudher
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Protein Tau ◽  
Neurodegenerative Process ◽  
Abnormal Hyperphosphorylation ◽  
Ad Alzheimer’S Disease ◽  
The Relationship ◽  
Shed Light ◽  
Drosophila Models

AD (Alzheimer's disease) is a neurodegenerative disorder characterized by the abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau and the misfolding and deposition of Aβ peptide. The mechanisms by which tau and Aβ become abnormal is not clearly understood, neither is it known what role either protein plays in the neurodegenerative process underlying AD. We have modelled aspects of AD in Drosophila melanogaster to shed light on these processes and to further our understanding of the relationship between tau and amyloid in this disease.

scholarly journals Tau seeding activity anticipates phospho-tau pathology in Alzheimer’s disease

2018 ◽  
Author(s):  
Sarah K. Kaufman ◽  
Kelly Del Tredici ◽  
Talitha L. Thomas ◽  
Heiko Braak ◽  
Marc I. Diamond
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Visual Cortex ◽  
Brain Regions ◽  
Tau Pathology ◽  
Age Related ◽  
Important Addition ◽  
Disease Stages ◽  
Relationship Of ◽  
The Relationship

AbstractAlzheimer’s disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological “seeds” may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegeneration remains obscure. Consequently, we employed an established cellular biosensor assay to quantify tau seeding activity in fixed human tissue, in parallel with AT8 phospho-tau staining of immediately adjacent sections. We studied four brain regions from each of n=247 individuals across a range of disease stages. We detected the earliest and most robust seeding activity in the TRE/EC. The LC did not uniformly exhibit seeding activity until later NFT stages. We also detected seeding activity in the first temporal gyrus and visual cortex at stages before NFTs and/or AT8-immunopositivity were detectable. AD and putative PART cases exhibited similar patterns of seeding activity that anticipated histopathology across all NFT stages. Our findings are consistent with the prion model and suggest that pathological seeding activity begins in the TRE/EC rather than in the LC, and may offer an important addition to classical histopathology.

scholarly journals Caspase-6-cleaved tau is relevant in Alzheimer’s disease but not in 4-repeat tauopathies: diagnostic and therapeutic implications

2021 ◽  
Author(s):  
Panos Theofilas ◽  
Antonia M.H. Piergies ◽  
Song Hua Li ◽  
Cathrine Petersen ◽  
Alexander J. Ehrenberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Strategy ◽  
Tau Pathology ◽  
Therapeutic Implications ◽  
Caspase 6 ◽  
Human Brains ◽  
The Relationship ◽  
Self Aggregation ◽  
Active Caspase

AbstractAimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation. Yet, the relationship between aCasp-6, different forms of tr-tau, and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer’s disease (AD) and other tauopathies remains unclear.MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in healthy controls, AD, and primary tauopathies.ResultsCasp-6 activation was strong in AD, followed by Pick’s disease (PiD), but almost absent in 4-repeat (4R) tauopathies. Tr-tau neuronal burden was much higher in AD than in 4R tauopathies, and disproportionally higher when normalizing by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, half of the tr-tau positive neurons in AD lacked p-tau aggregates.ConclusionsEarly modulation of aCasp-6 with consequent amortization of tr-tau pathology is a promising therapeutic strategy in AD and possibly PiD, but it is unlikely to benefit 4R tauopathies. The large percentage of tr-tau neurons lacking p-tau suggests that not all tau pathology and vulnerable neurons are detected by conventional p-tau Ser 202 antibody and, that AD, has distinct mechanisms of tangle formation. Therapeutic strategies against tr-tau pathology could modulate tau abnormalities in AD. The disproportional higher burden of tr-tau in AD supports the evaluation of biofluid biomarkers against N-terminus tr-tau to detect AD and differentiate it from 4R tauopathies at a single patient level.

Molecular Insight into the Crosstalk of UPS Components and Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1193-1201
Author(s):  
Abdullah Al Mamun ◽  
Md. Mosiqur Rahman ◽  
Sonia Zaman ◽  
Mst Shirajum Munira ◽  
Md. Sahab Uddin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Early Stage ◽  
Therapeutic Interventions ◽  
Cellular Proteins ◽  
Synaptic Dysfunction ◽  
Main Components ◽  
The Relationship ◽  
Insight Into

: The ubiquitin (Ub)-proteasome system (UPS) targets various cellular proteins for degradation. It has been found that defects in the UPS play a crucial role in the pathogenesis of Alzheimer's disease (AD), as the existence of Ub immunoreactivity in AD-linked neuronal inclusions, including neurofibrillary tangles, is observed in all types of AD cases. Current investigations have shown that components of the UPS can be connected with the early stage of AD, which is characterized by synaptic dysfunction, and to the late phases of the disease, marked by neurodegeneration. Although the significance of UPS in the pathogenesis of AD has been emphasized, targeted treatment at the main components of these pathways has a great perspective in advancing new therapeutic interventions for AD. In this review, we emphasize the relationship between UPS and AD pathology. We also represent the recent therapeutic advancements targeting UPS components in AD.

scholarly journals Associations between different tau-PET patterns and longitudinal atrophy in the Alzheimer's disease continuum

2021 ◽  
Author(s):  
Rosaleena Mohanty ◽  
Daniel Ferreira ◽  
Agneta Nordberg ◽  
Eric Westman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Structural Mri ◽  
Tau Pathology ◽  
Discrete Subgroups ◽  
Cognitively Normal ◽  
Prodromal Ad ◽  
Tau Pet ◽  
The Relationship

INTRODUCTION: Different subtypes/patterns have been defined using tau-PET and structural-MRI in Alzheimer's disease (AD), but the relationship between tau pathology and atrophy remains unclear. Our goals were twofold: (a) investigate the association between baseline tau-PET patterns and longitudinal atrophy in the AD continuum; (b) characterize heterogeneity as a continuous phenomenon over the conventional notion using discrete subgroups. METHODS: In 366 individuals (amyloid-beta-positive: cognitively normal, prodromal AD, AD dementia; amyloid-beta-negative healthy), we examined the association between tau-PET patterns (operationalized as a continuous phenomenon and a discrete phenomenon) and longitudinal sMRI. RESULTS: We observed a differential association between tau-PET patterns and longitudinal atrophy. Heterogeneity, measured continuously, may offer an alternative characterization, sharing correspondence with the conventional subgrouping. DISCUSSION: Site and the rate of atrophy are modulated differentially by tau-PET patterns in the AD continuum. We postulate that heterogeneity be treated as a continuous phenomenon for greater sensitivity over the current/conventional discrete subgrouping.

scholarly journals The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease

2021 ◽  
Vol 141 (3) ◽  
pp. 341-358
Author(s):  
David C. Hondius ◽  
Frank Koopmans ◽  
Conny Leistner ◽  
Débora Pita-Illobre ◽  
Regina M. Peferoen-Baert ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Folding ◽  
Neurofibrillary Tangles ◽  
Ribosomal Proteins ◽  
Molecular Mechanisms ◽  
Disease Process ◽  
Protein Markers ◽  
Granulovacuolar Degeneration ◽  
Tau Pathology

AbstractGranulovacuolar degeneration (GVD) is a common feature in Alzheimer’s disease (AD). The occurrence of GVD is closely associated with that of neurofibrillary tangles (NFTs) and GVD is even considered to be a pre-NFT stage in the disease process of AD. Currently, the composition of GVD bodies, the mechanisms associated with GVD and how GVD exactly relates to NFTs is not well understood. By combining immunohistochemistry (IHC) and laser microdissection (LMD) we isolated neurons with GVD and those bearing tangles separately from human post-mortem AD hippocampus (n = 12) using their typical markers casein kinase (CK)1δ and phosphorylated tau (AT8). Control neurons were isolated from cognitively healthy cases (n = 12). 3000 neurons per sample were used for proteome analysis by label free LC–MS/MS. In total 2596 proteins were quantified across samples and a significant change in abundance of 115 proteins in GVD and 197 in tangle bearing neurons was observed compared to control neurons. With IHC the presence of PPIA, TOMM34, HSP70, CHMP1A, TPPP and VXN was confirmed in GVD containing neurons. We found multiple proteins localizing specifically to the GVD bodies, with VXN and TOMM34 being the most prominent new protein markers for GVD bodies. In general, protein groups related to protein folding, proteasomal function, the endolysosomal pathway, microtubule and cytoskeletal related function, RNA processing and glycolysis were found to be changed in GVD neurons. In addition to these protein groups, tangle bearing neurons show a decrease in ribosomal proteins, as well as in various proteins related to protein folding. This study, for the first time, provides a comprehensive human based quantitative assessment of protein abundances in GVD and tangle bearing neurons. In line with previous functional data showing that tau pathology induces GVD, our data support the model that GVD is part of a pre-NFT stage representing a phase in which proteostasis and cellular homeostasis is disrupted. Elucidating the molecular mechanisms and cellular processes affected in GVD and its relation to the presence of tau pathology is highly relevant for the identification of new drug targets for therapy.

Liquid crystalline ordering of paired helical filaments in neurofibrillary tangles of Alzheimer's disease

1986 ◽  
Vol 44 ◽  
pp. 348-349
Author(s):  
D.F. Clapin ◽  
V.J.A. Montpetit
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Liquid Crystalline ◽  
Amyloid Fibrils ◽  
Geometric Analysis ◽  
Paired Helical Filaments ◽  
Microscopic Level ◽  
Light Microscopic Level ◽  
Regular Spacing

Alzheimer's disease is characterized by the accumulation of abnormal filamentous proteins. The most important of these are amyloid fibrils and paired helical filaments (PHF). PHF are located intraneuronally forming bundles called neurofibrillary tangles. The designation of these structures as "tangles" is appropriate at the light microscopic level. However, localized domains within individual tangles appear to demonstrate a regular spacing which may indicate a liquid crystalline phase. The purpose of this paper is to present a statistical geometric analysis of PHF packing.

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