Detection of d-aspartate in tau proteins associated with Alzheimer paired helical filaments

Kenessey, Ágnes; Yen, Shu Hui; Liu, Wan Kyng; Yang, Xiao Ran; Dunlop, David S.

doi:10.1016/0006-8993(95)00061-t

Cited by 35 publications

(14 citation statements)

References 33 publications

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“…The second possibility, as noted above, is also supported by a recent study reporting loss of hippocampal CA1 neurons following 25 μg tau PFF injection into the hippocampus of Tg overexpressing tau with P301L mutation [37]. Together with studies estimating that NFT-bearing neurons can survive for years or even decades in human brains [7, 27, 35], our current data suggest that NFTs are capable of causing neurodegeneration even though they normally do not kill cells in an acute manner unless a sudden burst of high NFT burden is induced under certain experimental paradigms.…”

Section: Discussionmentioning

confidence: 70%

Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections

et al. 2015

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Filamentous tau inclusions are hallmarks of Alzheimer’s disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed [25] that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle bearing neurons gradually cleared tau pathology by 6–12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique opportunities to elucidate mechanisms underlying the selective vulnerability of neurons to acquire tau pathology and succumb to or resist tau-mediated neurodegeneration.

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Section: Discussionmentioning

confidence: 70%

Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections

et al. 2015

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“…Observed in (Kenessey et al 1995 Nitration of tyrosine by reactive Not reported Elevated 3-nitrotyrosine in nitrating species produced neurofilaments from ALS cases by nitric oxide synthase (Strong 1999) In neurons, tau may have other, more specific functions, rather than simply serving as an inducer of microtubule assembly, an activity that is shared by many other neuronal and non-neuronal microtubule-associated proteins. Evidence for a specific role in the axon comes from its distribution during the development of neuronal polarity in vitro.…”

Section: Tau Pathology In Admentioning

confidence: 96%

Cytoskeletal mechanisms of neuronal degeneration

Brandt

2001

Cell Tissue Res

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The cytoskeleton is the major intracellular determinant of neuronal morphology and is required for fundamental processes during the development and maintenance of a neuron. Thus, it is not surprising that many neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis (motor neuron disease) are characterized by typical abnormalities in the organization of the cytoskeleton. However, the role of the cytoskeletal changes during the development of the disease, e.g., whether they have a causative role during neuronal degeneration or represent an epiphenomenon of neurons that degenerate by other means, is still disputed. In this review, recent results on the development and the role of cytoskeletal abnormalities during neurodegenerative diseases are discussed and a mechanistic framework for the involvement of cytoskeletal changes during neurodegenerative processes is presented.

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“…There has also been more racemized Asp found in tauprotein (Kenessey et al, 1995) and neurofibrillary tangles (NFTs) (Fisher et al, 1991b). The cerebrospinal fluids contain more asp and other D-amino acids in these patients than in normal controls (Fisher ef al., 1994).…”

Section: D-amlna Adds In Patientsmentioning

confidence: 97%