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      Molecular Pathogenesis of the Tauopathies

      Author(s): 1 , 2 , 1
      Publication date Created:
      Publication date (Print):
      Journal: Annual Review of Pathology: Mechanisms of Disease
      Publisher: Annual Reviews

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          Abstract

          The tauopathies constitute a group of diseases that have Tau inclusions in neurons or glia as their common denominator. In this review, we describe the biochemical and histological differences in Tau pathology that are characteristic of the spectrum of frontotemporal lobar degeneration as primary tauopathies and of Alzheimer's disease as a secondary tauopathy, as well as the commonalities and differences between the familial and sporadic forms. Furthermore, we discuss selected advances in transgenic animal models in delineating the different pathomechanisms of Tau.

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          Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.

          P Arriagada, J H Growdon, E T Hedley-Whyte … (1992)
          We studied the accumulation of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 Alzheimer's disease patients who had been examined during life. We counted NFTs and SPs in 13 cytoarchitectural regions representing limbic, primary sensory, and association cortices, and in subcortical neurotransmitter-specific areas. The degree of neuropathologic change was compared with the severity of dementia, as assessed by the Blessed Dementia Scale and duration of illness. We found that (1) the severity of dementia was positively related to the number of NFTs in neocortex, but not to the degree of SP deposition; (2) NFTs accumulate in a consistent pattern reflecting hierarchic vulnerability of individual cytoarchitectural fields; (3) NFTs appeared in the entorhinal cortex, CA1/subiculum field of the hippocampal formation, and the amygdala early in the disease process; and (4) the degree of SP deposition was also related to a hierarchic vulnerability of certain brain areas to accumulate SPs, but the pattern of SP distribution was different from that of NFT.
          Article 0 comments Cited 625 times – based on 0 reviews     Review now
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            APP mouse models for Alzheimer's disease preclinical studies

            Hiroki Sasaguri, Per Nilsson, Shoko Hashimoto … (2017)
            Abstract Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.
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              Proteopathic tau seeding predicts tauopathy in vivo.

              Brandon Holmes, Jennifer L Furman, Thomas E Mahan … (2014)
              Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼ 300 fM) and synuclein (∼ 300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.
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                Author and article information

                Journal
                Title: Annual Review of Pathology: Mechanisms of Disease
                Abbreviated Title: Annu. Rev. Pathol. Mech. Dis.
                Publisher: Annual Reviews
                ISSN (Print): 1553-4006
                ISSN (Electronic): 1553-4014
                Publication date Created: January 24 2019
                Publication date (Print): January 24 2019
                Volume: 14
                Issue: 1
                Pages: 239-261
                Affiliations
                [1 ]Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St. Lucia Campus, Brisbane, Queensland 4072, Australia;
                [2 ]Brain and Mind Centre and Central Clinical School, Sydney Medical School, University of Sydney, New South Wales 2006, Australia
                Article
                DOI: 10.1146/annurev-pathmechdis-012418-012936
                PubMed ID: 30355155
                SO-VID: 204e766e-8b64-412c-8e6a-d7f0bbecb27d
                Copyright © © 2019
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