Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease

Vogel, Jacob W.; Iturria-Medina, Yasser; Strandberg, Olof; Smith, Ruben; Levitis, Elizabeth; Evans, Alan C.; Hansson, Oskar

doi:10.1038/s41467-020-15701-2

Cited by 327 publications

(266 citation statements)

References 74 publications

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“…This disconnect raises questions about whether local levels of the two proteins should be directly related, especially during preclinical stages of AD. There is growing evidence that AD pathology is strongly tied to both structural [29] and functional [13] network connectivity properties in the brain [28,32]. This suggests that abnormal levels of tau phosphorylation may additionally be regulated by the presence of pathological Abeta in distant but connected regions.…”

Section: Discussionmentioning

confidence: 99%

Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain

Horie

Barthélemy

Mallipeddi

et al. 2020

acta neuropathol commun

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Alzheimer's disease (AD) neuropathologic change is characterized by amyloid plaques and neurofibrillary tangles (NFTs) that consist of aggregated amyloid beta (Abeta) and hyperphosphorylated tau proteins (p-tau), respectively. Although the global relationship between Abeta and p-tau has been studied for decades, it is still unclear whether a regional correlation exists between Abeta and p-tau in the human brain. Recent studies in cerebrospinal fluid (CSF) have suggested that tau phosphorylation at specific sites such as T217 is modified at an early stage of AD when amyloid plaques become detectable. We applied biochemical and mass spectrometry methods in human brain samples with and without Abeta plaque pathology to measure site-specific phosphorylation occupancies in soluble and insoluble tau. Our quantitative results identified multiple residues specifically hyper-phosphorylated in AD, including at sites T111, T153, S184 (or S185), T205, S208, T217, S262, and S285 in brain soluble tau. In contrast, the most enriched phosphorylated residues in brain insoluble tau were T111,

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Section: Discussionmentioning

confidence: 99%

Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain

Horie

Barthélemy

Mallipeddi

et al. 2020

acta neuropathol commun

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“…It is well known that different neuropathological lesions such as Aβ, NFTs, or Lewy bodies can co-exist in the brains of AD patients (Braak and Braak, 1997;Hamilton, 2000), predicting cross protein interactions. Indeed, several studies have shown that the interaction between Aβ and tau can exaggerate AD pathology (Ribé et al, 2005;Bennett et al, 2017;He et al, 2018;Vergara et al, 2019) and that amyloid deposition, preceding the NFT formation, can actively influence tau spreading to neocortical regions (Braak and Braak, 1997;Hardy and Selkoe, 2002;Jacobs et al, 2018;Vogel et al, 2020). Furthermore, oligomeric forms of Aβ were found to be abundant in synapses of AD patients early in the disease before the appearance of phospo-tau at later stages, suggesting that soluble Aβ oligomers in synaptic terminals are associated with dementia onset and may initiate a cascade that drives phosphorylated tau accumulation and its synaptic spread (Bilousova et al, 2016).…”

Section: Protein Cross-seedingmentioning

confidence: 99%

Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer’s Disease

d’Errico

Meyer‐Luehmann

2020

Front. Aging Neurosci.

107

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Alzheimer's disease (AD) is pathologically defined by extracellular accumulation of amyloid-β (Aβ) peptides generated by the cleavage of amyloid precursor protein (APP), strings of hyperphosphorylated Tau proteins accumulating inside neurons known as neurofibrillary tangles (NFTs) and neuronal loss. The association between the two hallmarks and cognitive decline has been known since the beginning of the 20th century when the first description of the disease was carried out by Alois Alzheimer. Today, more than 40 million people worldwide are affected by AD that represents the most common cause of dementia and there is still no effective treatment available to cure the disease. In general, the aggregation of Aβ is considered an essential trigger in AD pathogenesis that gives rise to NFTs, neuronal dysfunction and dementia. During the process leading to AD, tau and Aβ first misfold and form aggregates in one brain region, from where they spread to interconnected areas of the brain thereby inducing its gradual morphological and functional deterioration. In this mini-review article, we present an overview of the current literature on the spreading mechanisms of Aβ and tau pathology in AD since a more profound understanding is necessary to design therapeutic approaches aimed at preventing or halting disease progression.

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“…The appearance of dystrophic neurites in a plaque, as a consequence of the microglial reaction to the Ab, in some way facilitates or permits the spread of tau aggregation from the limbic system into the cerebral neocortex [39][40][41]. Several lines of evidence support this idea: imaging studies show that tau spread is accelerated by the presence of Ab [41]; injection of human tau from AD brains into APP-knock in mice with tau-negative neuritic plaques forms tau aggregates initially in plaque-associated dystrophic neurites, before tangles appear [42]; and in humans, tau can aggregate initially in dendrites before tangles appear in the neuronal soma [43] (Figure 1). This 'collision' of Ab and tau, mediated by microglia, in the cerebral neocortex has devastating consequences in terms of promoting neurodegeneration and the consequent development of dementia.…”

Section: The Genetics Of Admentioning

confidence: 99%

Invited Review – Understanding cause and effect in Alzheimer's pathophysiology: Implications for clinical trials

Boche

Nicoll

2020

Neuropathology Appl Neurobio

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Invite Review-Understanding cause and effect in Alzheimer's pathophysiology: Implications for clinical trials Alzheimer's disease (AD) pathology is multi-faceted, including extracellular accumulation of amyloid-b (Ab), accumulation of tau within neurons, glial activation and loss of neurons and synapses. From a neuropathological perspective, usually at a single time-point and often at the end-stage of the disease, it is challenging to understand the cause and effect relationships between these components. There are at least four ways of trying to unravel these relationships. First, genetic studies demonstrate mutations that influence Ab production, but not tau, can initiate AD; whereas genetic variants influencing AD risk are related to innate immunity and lipid metabolism. Second, studies at early time points show that pathology begins decades before the onset of dementia and indicate different anatomical locations for initiation of Ab and tau accumulation. Third, cause and effect can be studied in experimental models, but most animal models do not fully replicate AD pathology. However, induced pluripotent stem cells (iPSCs) to study live human neurons has introduced a new perspective. Fourth, clinical trials may alter AD pathology giving insights into cause and effect relationships. Therefore, a sequence of (i) neocortical Ab accumulation followed by (ii) a microglial inflammatory reaction to Ab, causing neuritic dystrophy which promotes (iii) spread of tau from the limbic system to the neocortex with (iv) progressive tau accumulation and spread resulting in (v) neurodegeneration, explains the evidence. It is proposed that different therapeutic targets are required for different stages of the disease process: Ab for primary prevention, microglia for secondary prevention, and tau for established disease.

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Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease

Cited by 327 publications

References 74 publications

Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain

Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain

Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer’s Disease

Invited Review – Understanding cause and effect in Alzheimer's pathophysiology: Implications for clinical trials

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