The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model

Li, Tong; Braunstein, Kerstin E.; Zhang, Juhong; Lau, Ashley; Sibener, Leslie; Deeble, Christopher; Wong, Philip C.

doi:10.1038/ncomms12082

Cited by 67 publications

(89 citation statements)

References 71 publications

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“…Some c-hGH samples have been found to contain tau (Duyckaerts et al, 2018). Furthermore, experimental studies show that tau polymerization can be cross-seeded by aggregated Aβ (Vasconcelos et al, 2016) and that tauopathy is augmented by Aβ plaques in vivo (Pooler et al, 2015; Li et al, 2016). …”

Section: Prion-like Seeding and Ad Pathology In Humansmentioning

confidence: 99%

Prion-like mechanisms in Alzheimer disease

Walker

2018

Handbook of Clinical Neurology

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Senile plaques and neurofibrillary tangles are the principal histopathologic hallmarks of Alzheimer disease. The essential constituents of these lesions are structurally abnormal variants of normally generated proteins: Aβ protein in plaques and tau protein in tangles. At the molecular level, both proteins in a pathogenic state share key properties with classic prions, i.e., they consist of alternatively folded, β-sheet-rich forms of the proteins that autopropagate by the seeded corruption and self-assembly of like proteins. Other similarities with prions include the ability to manifest as polymorphic and polyfunctional strains, resistance to chemical and enzymatic destruction, and the ability to spread within the brain and from the periphery to the brain. In Alzheimer disease, current evidence indicates that the pathogenic cascade follows from the endogenous, sequential corruption of Aβ and then tau. Therapeutic options include reducing the production or multimerization of the proteins, uncoupling the Aβ-tauopathy connection, or promoting the inactivation or removal of anomalous assemblies from the brain. Although aberrant Aβ appears to be the prime mover of Alzheimer disease pathogenesis, once set in motion by Aβ, the prion-like propagation of tauopathy may proceed independently of Aβ; if so, Aβ might be solely targeted as an early preventive measure, but optimal treatment of Alzheimer disease at later stages of the cascade could require intervention in both pathways.

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Section: Prion-like Seeding and Ad Pathology In Humansmentioning

confidence: 99%

Prion-like mechanisms in Alzheimer disease

Walker

2018

Handbook of Clinical Neurology

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“…Defects in retrograde transport of lysosomal vesicles along the axon have been causally linked to increased amyloid plaque burden in mouse models of Alzheimer's disease (Ye et al ., ). Neuritic plaques also accelerate the pathogenic aggregation of tau (Li et al ., ), further emphasising the importance of studying these structures.…”

Section: Introductionmentioning

confidence: 99%

Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus

Hassiotis

Manavis

Blumbergs

et al. 2018

Eur J of Neuroscience

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Lysosomal vesicles around neuritic plaques are thought to drive Alzheimer's disease by providing ideal microenvironments for generation of amyloid-β. Although lysosomal vesicles are present at every amyloid plaque in mouse models of Alzheimer's disease, the number of amyloid plaques that contain lysosomal vesicles in the human brain remains unknown. This study aimed to quantify lysosomal vesicles at amyloid plaques in the human hippocampus. Lysosome-associated membrane protein 1 (LAMP1)-positive vesicles accumulated in both diffuse (Aβ42-positive/AT8-negative) and neuritic (Aβ42-positive/AT8-positive) plaques in all regions were analysed. In contrast to mouse models of Alzheimer's disease, however, not all amyloid plaques accumulated LAMP1-positive lysosomal vesicles. Even at neuritic plaques, LAMP1 immunoreactivity was more abundant than phospho-tau (AT8). Further, lysosomal vesicles colocalised weakly with phospho-tau such that accumulation of lysosomal vesicles and phospho-tau appeared to be spatially distinct events that occurred within dystrophic neurites. This quantitative study shows that diffuse plaques, as well as neuritic plaques, contain LAMP1 immunoreactivity in the human hippocampus.

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“…Notably, deregulation of body temperature is well characterized to promote Tau pathology in vivo [93-96]. Hyperphosphorylated Tau as well as NFTs [97] and atrophy [98] in the hypothalamus have also been reported in mouse models of tauopathies.…”

Section: Overview On Tau and Tauopathiesmentioning

confidence: 99%

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

et al. 2018

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Alzheimer disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments, and lower brain glucose metabolism, which often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood. Insulin is a hormone involved in the control of energy homeostasis both peripherally and centrally, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that insulin resistance can exacerbate Tau lesions, mainly by disrupting the balance between Tau kinases and phosphatases. On the other hand, the emerging literature indicates that Tau protein can also modulate insulin signalling in the brain, thus creating a detrimental vicious circle. The following review will highlight our current understanding of the role of insulin in the brain and its relation to Tau protein in the context of AD and tauopathies. Considering that insulin signalling is prone to be pharmacologically targeted at multiple levels, it constitutes an appealing approach to improve both insulin brain sensitivity and mitigate brain pathology with expected positive outcome in terms of cognition.

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The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model

Cited by 67 publications

References 71 publications

Prion-like mechanisms in Alzheimer disease

Prion-like mechanisms in Alzheimer disease

Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

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