Dataset Information

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

ABSTRACT:

Background

The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([¹⁸F]flortaucipir PET), synaptic density (synaptic vesicle 2A [¹¹C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease.

Methods

Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [¹⁸F]flortaucipir PET, dynamic 60-min [¹¹C]UCB-J PET with arterial sampling and 2?×?5-min resting-state MEG measurement. [¹⁸F]flortaucipir- and [¹¹C]UCB-J-specific binding (binding potential, BP_ND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [¹⁸F]flortaucipir BP_ND, [¹¹C]UCB-J BP_ND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models.

Results

Across subjects, higher regional [¹⁸F]flortaucipir uptake was associated with lower [¹¹C]UCB-J uptake. Within subjects, the association between [¹¹C]UCB-J and [¹⁸F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [¹⁸F]flortaucipir and lower [¹¹C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe.

Conclusions

These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

SUBMITTER: Coomans EM

PROVIDER: S-EPMC7866464 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

Coomans Emma M EM Schoonhoven Deborah N DN Tuncel Hayel H Verfaillie Sander C J SCJ Wolters Emma E EE Boellaard Ronald R Ossenkoppele Rik R den Braber Anouk A Scheper Wiep W Schober Patrick P Sweeney Steven P SP Ryan J Michael JM Schuit Robert C RC Windhorst Albert D AD Barkhof Frederik F Scheltens Philip P Golla Sandeep S V SSV Hillebrand Arjan A Gouw Alida A AA van Berckel Bart N M BNM

Alzheimer's research & therapy 20210205 1

<h4>Background</h4>The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([<sup>18</sup>F]flortaucipir PET), synaptic density (synaptic vesicle 2A [<sup>11</sup>C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease.<h4>Methods</h4>Seven amyloid-positive Alzhe ...[more]

PMID: 33546722

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Project description:Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.

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Dataset Information

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

Background

Methods

Results

Conclusions

Publications

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

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