Dementia Advances in Two Phases, Suggests New Drexel-Led Study

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Dementia Advances in Two Phases, Suggests New Drexel-Led Study

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Dementia symptoms progress in multiple stages of preclinical, mild, moderate, and severe without following a strict linear path. Now a recently published study in the journal Alzheimer's and Dementia, led by researchers at Drexel University's College of Medicine, reveals new insights about what is happening to tau and brain cells during the progression of tau-associated disease, suggesting that dementia advances in two phases. The findings also build a case for better understanding microtubule changes as a basis for phase-specific therapies against frontotemporal dementia (FTD) and potentially other tau-related brain diseases.

For context, dementia research has largely contered on the role of tau proteins, which help to regulate the activities of nerve cells. Specifically, in properly-functioning brains, tau proteins help regulate the dynamics of small, hollow protein tubes within nerve cells -known as microtubules - that help the cell keep its shape so it can move nutrients, assist in cell signaling and memory development, among other functions. The brain uses these nerve cells, called neurons, to send messages to the rest of the body via electrical and chemical signals.

In tau-related brain diseases, such as FTD, these tau fibers become tangled, detach from these microtubules and form aggregates, damaging nerve cells and causing the memory and body movement deficits that are hallmarks of these diseases. But new findings from researchers in Drexel University's College of Medicine suggest that changes in the of microtubules -characterized by their continuous and random transitions between phases of growth, shortening, and pause- from the early phase of dementia to its later stages, triggered by these tau mutations, may shift our understanding of dementia's progression and how it might be treated.

This dynamic instability, which allows microtubules to rapidly reorganize in response to cellular demands, is essential for maintaining neuronal structure, intracellular transport, axonal growth, synaptic plasticity, and other neuronal functions.

"Suggesting that a progressive loss of tau simply causes microtubule destabilization misses the full picture," said senior author Liang Oscar Qiang, MD, PhD, a faculty member in the College of Medicine. "Our findings suggest that researchers should focus on preserving or creating the right balance of functionally available tau, MAP6 and overall architecture of microtubules."

In the paper, the researchers used three isogenic sets of brain organoids - 3-D tissue models grown in a lab from human stem cells - and tracked development of tau over eight months. These organoids included gene mutations, called MAPT, that guide the cells to create tau. Using biochemical imaging and electrophysiological techniques to track tau microtubules, the team analyzed brain cell activity over eight months and found a change in the of microtubules from the early phase of dementia to its later stages, triggered by these tau mutations.

They found that that the three MAPT mutations examined initially increased tau production and microtubule dynamicity or , which is the susceptibility of microtubules to disassembly or remodeling. For example, more labile microtubules are less stable and turn over more readily. They are kind of similar and sometimes interchangable with very nuance differences . As the disease progressed, phosphates accumulated on the tau proteins - a condition called hyperphosphorylation - and as they detached from microtubules, the tau accumulated into insoluble aggregates, reducing the pool of functionally available tau.

This loss of soluble, functional tau was accompanied by a shift toward abnormally stable microtubules, revealing a two-phase progression from early microtubule hyperdynamicity to late-stage microtubule hyperstability.

"We saw increases in tau and a drop in MAP6 - a microtubule-associated protein that indeed stabilizes microtubules in the cells - within the first month in our organoid models," Qiang said. "This is sort of a yin and yang between these two proteins. But in late-stage disease, the tau became more insoluble and less functional as MAP6 increased."

In early-stage tau-related disease, the authors found, the high levels of tau, that otherwise would help protect microtubules, instead become toxic, destabilizing brain cells and making the microtubules more dynamic even before noticeable neurodegeneration.

As the disease progressed, the balance flips during the next phase, where the microtubules actually become too stable, MAP6 protein dominates and leads to cellular dysfunction. Notably, at the eight-month mark, the researchers discovered that this rise in MAP6 was found in signaling cells, known as neurons, and not in the glial cells that protect the neurons.

"Excessively stable microtubules can be harmful in tau-related diseases because they lose the plasticity needed for healthy nerve-cell function," Qiang said. "We find that in late-stage disease, and in post-mortem tissue, if you look at the microtubule compensation, what's left in the brain is mostly stable microtubules. Dynamic microtubules, which are critical for synaptic plasticity and axonal transport, are mostly gone. We see that tau mutations trigger changes in microtubule dynamics throughout different phases of the disease."

In the paper, the team speculated that in the disease may help rescue hyperactive brain cells, but that further research that directly measures the exact amount of tau and MAP6 is needed to more accurately assess how these proteins compete to control the activity of neurons.

The authors added that future long-term studies with cell-type-specific analyses are needed to refine this model, but that the groundwork in this paper suggests that great success can be derived from early intervention with tau-lowering approaches and later interventions that restore functional tau-microtubule interactions, reduce MAP6 or fix hyperstable microtubules.

The team is currently working on more sophisticated organoid models, incorporating additional cell types, like microglia and endothelial cells, to study neuroinflammation and microvasculature deficits in tau pathology.

Qiang said there may be opportunities to develop therapies that try to preserve stability in microtubules early in disease onset and/or convert some stable microtubules to dynamic ones in more advanced dementia cases.

In addition to Qiang, other study authors include lead author Xiaohuan Sun, Skandha Ramakrishnan, Victor C Ogbolu, from Drexel; Nicholas M Kanaan from Michigan State University; Celeste M Karch from Washington University in St. Louis and Peter W Baas from Drexel.

This research was supported by grants from the Lisa Dean Moseley Foundation, Alzheimer's Association, National Institutes of Health, Rainwater Charitable Organization and U.S. Department of War.

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