Abstract

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.

Highlights

  • 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

  • Since tau pathology consistently begins in the entorhinal cortex (EC) in human AD brains, we hypothesized that tau seeding in the EC of Low Braak patients is a predictor of further developing tau pathology

  • HEK239-TauRD -cyan fluorescent protein (CFP)/yellow fluorescent protein (YFP) seeding cells can be detected in the EC of Low Braak cases despite there being only rare tau pathology. (C) Representative photos of induced tau aggregates in the HEK239-TauRD -CFP/YFP cells

Read more

Summary

INTRODUCTION

Formation, posterior parahippocampal gyrus, anterior cingulate cortex, visual association area, and culminate in the primary visual cortex. As tau imaging markers have evolved, additional studies have been performed looking at the deposition of tau pathology in association with brain atrophy using positron emission tomography (PET) in living patients, finding that the formation of tau pathology—as defined by tau PET ligand binding—occurs along the immunohistologically described Braak Tau Pathway and directly correlates with neuronal dysfunction and loss (Ishiki et al, 2015; Ossenkoppele et al, 2016; Schöll et al, 2016; Sepulcre et al., 2016; Hoenig et al, 2018; Iaccarino et al, 2018) These studies demonstrate that NFTs systematically form first in layer 2 of the entorhinal cortex and, from there, progress to the hippocampal

MATERIALS AND METHODS
RESULTS
DISCUSSION
ETHICS STATEMENT

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.