Does Tau Aggregation Spread from Region to Region in the Aging Brain?
The tau protein is involved in maintaining stability of microtubule structures in the axons that connect neurons. It isn't the only protein that undertakes this task, and loss of functional tau doesn't produce immediate issues. Tau is important in some functions of memory, however, and mice lacking tau exhibit a range of cognitive defects that grow with age. Tau is well studied not for these aspects of its function, but because it is one of the few proteins that can be altered in a way that allows it to form solid aggregates that are disruptive to cell function. Tau aggregation to form the structures known as neurofibrillary tangles is a feature of late stage Alzheimer's disease. The consensus view of this stage of the condition is that tau aggregation and chronic inflammation form a feedback loop that accelerates dysfunction into widespread cell death in the brain.
The progression of Alzheimer's disease provides the appearance of a spread of tau aggregation from region to region in the brain. Study of the brain is challenging, however, and while there is a consensus on this point - that altered forms of tau can seed more dysfunction in a prion-like way and spread from cell to cell via synapses - there are other potential explanations for the observed outcomes. For example tau aggregation could be universal in the brain, but some regions are more vulnerable to the aggregation processes than others, and therefore exhibit a greater burden of neurofibrillary tangles earlier in the progression of the condition. Today's open access paper is an example of the way in which researchers must strive to circumvent the inability to directly access a large number of living human brains at various stages of Alzheimer's disease. Instead, the researchers synthesize a number of indirect approaches - models, genetics, postmortem tissues, and imaging data - to produce supporting evidence for the consensus view of a synaptic spread of tau aggregation.
Tau protein promotes assembly and stabilization of microtubules. In normal aging and Alzheimer's disease (AD), tau can become hyperphosphorylated, which reduces its affinity for microtubules and drives its mislocalization from axons to the body of the neuron and dendrites. Aberrant tau accumulation in the form of neurofibrillary tangles (NFTs) is a strong pathological correlate of cognitive decline. Based on postmortem human brain studies, the spatiotemporal progression of NFTs begins in layers II and III of the entorhinal cortex (EC), extends to the hippocampus and temporal cortex, entering the limbic system before reaching broader neocortical regions, which subsequent tau positron emission tomography (PET) studies confirmed in vivo. When tau is confined to the medial temporal lobe, patients typically experience memory problems, but once tau enters the neocortex, broader cognitive impairment often emerges.
The mechanisms underlying tau spread are unclear, but may rely on a process, referred to as tau seeding, in which abnormal forms of tau protein induce misfolding and aggregation of normal tau proteins in a template-dependent manner. Prior studies using cell cultures, mouse models, and human neuroimaging have each explored certain facets of tau pathology progression. However, whether endogenous tau seeds are the entities that induce NFTs across the aging human brain via naturally occurring connectivity remains to be confirmed. An alternative hypothesis that accounts for the observed NFT distribution is a gradient in region vulnerability, which does not involve tau seeds spreading from early-affected regions.
To investigate this question, we measured tau seed bioactivity data in synaptosomes from postmortem inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) tissues of 128 individuals and combined this data with genotype and antemortem fMRI measurements from the same individuals. Via multimodal integration of these data, we provided supporting evidence that tau seeds from an early-affected brain region induce local NFTs as well as drive tau seeds and NFTs in a late-affected, far-removed region. Also, extending past tau-PET studies that demonstrated spatial correspondence between tau deposition and connectivity patterns, we further showed that individual-specific intrinsic connectivity modulates tau seed-NFT relationships. Our results thus support the hypothesis that tau seeds use synaptic connections to spread tau across connected regions in the human brain.