Synergy between amyloid-β and tau in Alzheimer’s disease

Busche, Marc Aurel; Hyman, Bradley T.

doi:10.1038/s41593-020-0687-6

Cited by 650 publications

(512 citation statements)

References 153 publications

(220 reference statements)

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“…In CU individuals, positive Aβ status and older age were the strongest predictors of tau PET positivity in the entorhinal cortex and temporal meta-ROI. This is in line with an extensive literature on the interplay between Aβ and tau pathology in aging populations, suggesting that amyloid-β facilitates the neocortical spread of tau pathology [51]. In addition, there is evidence for a (possibly Aβ-independent) effect of advancing age on tau accumulation in the medial temporal lobe, which would explain why older age was only associated with tau PET positivity in the entorhinal cortex and temporal meta-ROI, but not in the Braak V-VI ROI.…”

Section: Discussionsupporting

confidence: 90%

The impact of demographic, clinical, genetic, and imaging variables on tau PET status

Ossenkoppele

Leuzy

Cho

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) are tau PET–negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET–positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status. Methods We included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model. Results Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan. Conclusion We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.

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Section: Discussionsupporting

confidence: 90%

The impact of demographic, clinical, genetic, and imaging variables on tau PET status

Ossenkoppele

Leuzy

Cho

et al. 2020

Eur J Nucl Med Mol Imaging

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“…The interaction between pathological proteins including tau, Aβ, α‐synuclein and prion, is an active area of study (Busche & Hyman, 2020), given their co‐occurrence in protein aggregates observed in post‐mortem brain samples of patients diagnosed with different neurodegenerative diseases (Spires‐Jones, Attems, & Thal, 2017). Recent work demonstrates mechanistic crosstalk between these proteins also in transcellular spread.…”

Section: Mechanisms For Neuronal Entry Of Taumentioning

confidence: 99%

Knockin’ on heaven’s door: Molecular mechanisms of neuronal tau uptake

La-Rocque

Moretto

Butnaru

et al. 2020

Journal of Neurochemistry

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Since aggregates of the microtubule‐binding protein tau were found to be the main component of neurofibrillary tangles more than 30 years ago, their contribution to neurodegeneration in Alzheimer's disease (AD) and tauopathies has become well established. Recent work shows that both tau load and its distribution in the brain of AD patients correlate with cognitive decline more closely compared to amyloid plaque deposition. In addition, the amyloid cascade hypothesis has been recently challenged because of disappointing results of clinical trials designed to treat AD by reducing beta‐amyloid levels, thus fuelling a renewed interest in tau. There is now robust evidence to indicate that tau pathology can spread within the central nervous system via a prion‐like mechanism following a stereotypical pattern, which can be explained by the trans‐synaptic inter‐neuronal transfer of pathological tau. In the receiving neuron, tau has been shown to take multiple routes of internalisation, which are partially dependent on its conformation and aggregation status. Here, we review the emerging mechanisms proposed for the uptake of extracellular tau in neurons and the requirements for the propagation of its pathological conformers, addressing how they gain access to physiological tau monomers in the cytosol. Furthermore, we highlight some of the key mechanistic gaps of the field, which urgently need to be addressed to expand our understanding of tau propagation and lead to the identification of new therapeutic strategies for tauopathies.

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“…Our findings identified the Wnt/PCP pathway as a synaptic target of Aβ-associated synaptotoxicity, a process thought to start long before the appearance of cognitive symptoms and may provide new clues to understand pathogenesis. Our findings do not exclude the possibility that the PCP pathway may also be involved in tauopathy-mediated synapse degeneration, which likely occur at a later time, a topic we plan to explore in the future 11 . Furthermore, our discovery of a direct synaptic target in mediating Aβ oligomer- induced synapse loss does not exclude or contradict the possibility of other mechanisms, such as by complement and microglia 31 .…”

Section: Discussionmentioning

confidence: 65%

“…Increased Aβ seeding and reduced Aβ clearance appear to be related to the risk, suggesting APOE4 may affect AD risk, at least in part, by regulating amyloid pathology 8 9 10 . The relationship between β−amyloid pathology and tauopathy, which corelates better with the progression of cognitive impairment, has not been sorted out as to which one is causal or whether they actually synergize 11 . Therefore, we elected to focus on an amyloid-dependent event that occurs before tauopathy is fully developed, the initial loss of glutamatergic synapses 12 .…”

mentioning

confidence: 99%

Protecting synapses from amyloid β-associated degeneration by manipulations of Wnt/planar cell polarity signaling

Feng¹,

Freitas²,

Tian³

et al. 2020

Preprint

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Synapse loss is an early event in Alzheimer’s disease and is thought to be associated with amyloid pathology and caused by Amyloid β (Aβ) oligomers. Whether and how Aβ oligomers directly target signaling pathways for glutamatergic synapse maintenance is unknown. Glutamatergic synapse development is controlled by the opposing functions of Celsr3 and Vangl2, core components of the Wnt/planar cell polarity (PCP) signaling pathway, functioning directly in the synapses. Celsr3 promotes synapse formation, whereas Vangl2 inhibits synapse formation. Here we show that oligomeric Aβ binds to Celsr3 and assists Vangl2 in disassembling synapses by disrupting the intercellular Celsr3/Frizzled3-Celsr3 complex, essential for PCP signaling. Together with Vangl2, a Wnt receptor, Ryk, is also required for Aβ oligomer-induced synapse loss in a mouse model of Alzheimer’s disease, 5XFAD, where conditional Ryk knockout protected synapses and preserved cognitive function. Our study reveals a fine balance of Wnt/PCP signaling components in glutamatergic synapse maintenance and suggests that overproduced Aβ oligomers may lead to excessive synapse loss by tipping this balance. Together with previous reports that an inhibitor of Wnt/Ryk signaling, WIF1, is found reduced in Alzheimer’s disease patients, our results suggest that the imbalance of PCP signaling in these patients may contribute to synapse loss in Alzheimer’s disease and manipulating Wnt/PCP signaling may preserve synapses and cognitive function.

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Synergy between amyloid-β and tau in Alzheimer’s disease

Cited by 650 publications

References 153 publications

The impact of demographic, clinical, genetic, and imaging variables on tau PET status

The impact of demographic, clinical, genetic, and imaging variables on tau PET status

Knockin’ on heaven’s door: Molecular mechanisms of neuronal tau uptake

Protecting synapses from amyloid β-associated degeneration by manipulations of Wnt/planar cell polarity signaling

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