Fight Aging!

LATE is a comparatively recently discovered form of dementia, connected to aggregation of misfolded TDP-43, one of the few proteins in the body capable of taking on an altered form that encourages other molecules of the same protein to also adopt that form and join together to form clumps. Aggregates are disruptive of cell function, but it is a slow process to understand exactly why this is the case. Researchers have been working on understanding amyloid-β aggregates for decades now, and continue to find that the present state of knowledge is incomplete regarding how the toxic halo of biochemistry that surrounds aggregates causes dysfunction and cell death.

With the growing interest in TDP-43 pathology, researchers have in recent years found it present in many older people to a measurable degree, as is the case for other protein aggregates. It is important to work towards therapies that can clear all of these aggregates, such as potentially those based on the use of catabodies. Even in the absence of very obvious pathology, it is likely the case that protein aggregates contribute to brain aging in more subtle, indirect ways. Medin aggregates, for example, have only recently been found to likely cause pathology, and they have been known for decades.

Looking for an Early Sign of LATE

Limbic predominate age-related TDP-43 encephalopathy or LATE is a recently recognized form of dementia that affects memory, thinking, and social skills. It mimics Alzheimer's disease or AD (and sometimes co-exists with it), but LATE is a different condition, with its own risks and causes. A new study analyzed levels of TDP-43 extracted from the exosomes secreted into the blood stream by various cell types, including neurons and glial cells. Exosomes are extracellular vesicles or sacs that transport DNA, RNA, and proteins inside the cell until their release. Researchers analyzed the brains of 64 patients post-mortem, 22 with autopsy-confirmed LATE and 42 patients who died without an indication of LATE.

The researchers reported significantly elevated plasma levels of TDP-43 in confirmed LATE patients. The effect was detected only in astrocyte-derived exosomes, not neuronal or microglial exosomes. Astrocytes are a sub-type of glial cell that perform many essential functions in the central nervous system, from regulating blood flow to providing the building blocks of neurotransmitters. They outnumber neurons more than fivefold. Effective treatment of all neurological diseases depends greatly upon early diagnosis. At the moment, however, LATE can only be diagnosed after death, and it is often confounded by the fact that living patients may have both LATE and AD. The findings that increased plasma concentrations of TDP-43 could be a tell-tale indicator of LATE are encouraging.

Evaluation of blood-based, extracellular vesicles as biomarkers for aging-related TDP-43 pathology

Limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC) is a recently characterized brain disease that mimics Alzheimer's disease (AD) clinically. TDP-43 was evaluated in neuronal (NDEVs), astrocyte (ADEVs), and microglial derived extracellular vesicles (MDEVs). EV preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses of disease.

TDP-43 was significantly elevated in plasma ADEVs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in EV-depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. Blood-based EVs, specifically measuring TDP-43 accumulation in ADEVs, may serve as a potential diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.