Neurofibrillary tangles, largely composed of tau protein, are one of the two pathological hallmarks of Alzheimer’s disease (AD), and are believed to be centrally involved in the neurodegenerative process. “For over 25 years, it has been clear that they accumulate in a hierarchical pattern within the brain,” says Brad Hyman, MD, PhD, beginning in the entorhinal cortex (EC) and followed by accumulation in the anatomically connected limbic and association cortices.
But it remains controversial whether that pattern of accumulation reflects cell-to-cell spreading of disease, or simply successive involvement of differentially resistant neuronal populations. Now, one new study from Dr. Hyman’s lab strongly suggests that AD involves a prion-like propagation from the EC outward, and a second shows that stopping or reversing this spread, and some of the damage it causes, may be a realistic therapeutic goal. Dr. Hyman is Director of the Alzheimer’s Disease Research Center (ADRC) at MGH.
To test whether tau pathology can spread, Dr. Hyman created a new mouse model in which mutant tau was expressed only in the neurons of the EC, the predominant input and output network of the hippocampal formation, and the earliest site of AD pathology. “Restricting the transgene expression to the entorhinal cortex allowed us to investigate whether pathological tau changes spread through neural circuits,” Dr. Hyman says, as predicted from pathological studies of AD brain at different stages. And that is in fact what their results showed; after several months, mutant tau propagated to the dentate gyrus and the anterior cingulate cortex, and accumulated in tangles along with endogenous, non-mutant mouse tau. Neurodegeneration ensued, and included neurons not expressing the mutant tau gene. In contrast, cortical areas not in direct contact with the EC did not display tau aggregates and remained unaffected.
“The mechanism of tau spread is still unknown,” Dr. Hyman says, "but if it is present in the extracellular space as free protein, rather than enclosed in a vesicle, it may be possible to target it with antibodies or another inactivating treatment.” If so, Dr. Hyman’s second new finding suggests at least some of the damage from tau accumulation can be reversed.
In the second study, he controlled mutant tau expression with an antibiotic-sensitive promoter, enabling him to turn the gene off by feeding the mice doxycycline. Mice were allowed to express the mutant gene for 18 months, by which time tau had begun to spread and accumulate in adjacent cells. “We took advantage of the ability to suppress the transgene expression using doxycycline to ask whether, once started, this process of tau protein propagation was irreversible or whether it could be intercepted by a tau-specific intervention,” Dr. Hyman says.
He found that after three months of gene suppression, aggregates in the dentate gyrus had decreased, and after six months they were almost completely absent. Neurofibrillary tangles were also reversed, along with compensatory neuronal sprouting in dysfunctional neurons.
“These results suggest an unexpected conclusion, that many of the neural system consequences of tau overexpression can be reversed or stabilized by suppression of tau expression, rather than being irreversible consequences of the formation of neurofibrillary tangles. While there is presumably a ‘point of no return’ after which neuronal death ensues,” Dr. Hyman says, “we think that some or all of these phenomena, long held to be end-stage pathology lesions in human AD, may be at least in part amenable to therapeutic intervention.”
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