Neurofibrillary changes undergoing morphological and biochemical changes – How does tau with the profile shift of from four repeat to three repeat spread in Alzheimer brain?

Uchihara, Toshiki

doi:10.1111/neup.12669

Cited by 13 publications

(12 citation statements)

References 37 publications

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“…Similar evolution of tau has been suggested for AD as well [ 18 , 39 ]. It was hypothesized that the elevated 3R density was correlated with the appearance of extracellular neurofibrillary tangle (NFT) pathology that was left behind after a neuron has died (ghost tangle) [ 8 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

Cherry

Esnault

Baucom

et al. 2021

acta neuropathol commun

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Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

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Section: Introductionmentioning

confidence: 99%

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

Cherry

Esnault

Baucom

et al. 2021

acta neuropathol commun

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“…Braak was the first to demonstrate a stereotypic distribution of neurofibrillary tangles (NFTs) and their progressive extension along a predefined sequence in Alzheimer disease (AD). This elegant observation led to a mechanistic interpretation that such lesion spreading is mediated by neuronal connections (Braak's scheme), as summarized by Uchihara in this symposium 3 . Tau protein is capable of replicating its pathogenicity by aggregating itself like prion.…”

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confidence: 98%

“…This elegant observation led to a mechanistic interpretation that such lesion spreading is mediated by neuronal connections (Braak's scheme), as summarized by Uchihara in this symposium. 3 Tau protein is capable of replicating its pathogenicity by aggregating itself like prion. This prion-like property may play a major role in propagating tau lesions (prion hypothesis based on experimental truths) along neural connections, as discussed by Hasegawa.…”

mentioning

confidence: 99%

“…Because this profile shift occurs along with regional spread of AD-NFT, it is considered to be a fundamental phenomenon underpinning AD pathogenesis, as discussed by Uchihara. 3 Because 3R and 4R isoforms are different molecules that are not mutually interchangeable, it is not possible for either 3R or 4R tau to undergo such profile shifts even if tau protein has the potential to aggregate by itself as prions do. Some agents other than tau itself may be necessary to explain this profile shift and its spreading.…”

mentioning

confidence: 99%

“…In the AD brain, gradual transition from four‐repeat (4R) tau in pretangle to three‐repeat (3R) tau in ghost tangle is consistent. Because this profile shift occurs along with regional spread of AD‐NFT, it is considered to be a fundamental phenomenon underpinning AD pathogenesis, as discussed by Uchihara 3 . Because 3R and 4R isoforms are different molecules that are not mutually interchangeable, it is not possible for either 3R or 4R tau to undergo such profile shifts even if tau protein has the potential to aggregate by itself as prions do.…”

mentioning

confidence: 99%

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Reconsidering the Braak–prion hypothesis: truths or realities

2020

Self Cite

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Characterization of neurofibrillary tangle immunophenotype signatures to classify tangle maturity in Alzheimer's disease

Hamlin,

Ryall,

Turner

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONTau aggregation into neurofibrillary tangles in Alzheimer's disease (AD) is a dynamic process involving changes in tau phosphorylation, isoform composition, and morphology. To facilitate studies of tangle maturity, we developed an image analysis pipeline to study antibody labeling signatures that can distinguish tangle maturity levels in AD brain tissue.METHODSUsing fluorescent immunohistochemistry, we co‐labeled AD brain tissue with four antibodies that bind different tau epitopes. Mean fluorescence intensity of each antibody was measured, and spectral clustering was used to identify tangle immunophenotypes.RESULTSFive distinct tangle populations were identified, and different tangle maturity immunophenotypes were identified with increasing Braak stage. Early tangle immunophenotypes were more prevalent in later affected regions and advanced immunophenotypes were associated with ghost morphology.DISCUSSIONOur findings indicate that tangle populations characterized by advanced tau immunophenotypes are associated with higher Braak stage and more mature morphology, providing a new framework for defining tangle maturity levels using tau antibody signatures.Highlights Populations of neurofibrillary tangles exist in Alzheimer's disease. The immunophenotype of neurofibrillary tangle populations relates to their maturity. The most advanced immunophenotypes are associated with higher Braak stage. The most advanced immunophenotypes are associated with ghost morphology. The most immature immunophenotypes are associated with later affected regions.

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Neurofibrillary changes undergoing morphological and biochemical changes – How does tau with the profile shift of from four repeat to three repeat spread in Alzheimer brain?

Cited by 13 publications

References 37 publications

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

Reconsidering the Braak–prion hypothesis: truths or realities

Characterization of neurofibrillary tangle immunophenotype signatures to classify tangle maturity in Alzheimer's disease

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