Title: Ultra Early Molecular Pathologies of Dementia

 

Hitoshi Okazawa, MD. PhD.

Senior Fellow, Emeritus Professor, Institute of Science Tokyo

 

Abstract

The “aggregation hypothesis,” which considers that insoluble disease protein aggregates are the cause of toxicity, has been used in many studies to elucidate pathology and develop treatments. For example, the “amyloid hypothesis” for Alzheimer’s disease (AD) is a representative example of the “aggregation hypothesis.” The recent commercialization of amyloid antibodies aimed at removing insoluble amyloid aggregates partially supports the correctness of the aggregation hypothesis, while the limited therapeutic effect in human patients also suggests the limitations of the aggregation hypothesis. For this reason, attention has been focused on “ultra-early molecular pathologies” caused by soluble disease proteins in a dissolved state before the formation of insoluble aggregates, such as liquid-liquid phase separation (LLPS) and neuronal cell death due to intracellular amyloid.

 

In response to growing interest in “ultra-early molecular pathologies,” this lecture will introduce two recently uncovered dementia pathologies. The first topic is cell death that occurs before aggregation. In recent years, three independent research results have reported brain pathological changes that occur before the formation of amyloid aggregates. The first paper confirmed that intracellular amyloid induced necrosis (TRIAD) due to the inhibition of YAP (the final effector of the Hippo signaling pathway) function, and the surrounding clusters of degenerated neurites filled with autolysosomes, are observed in disease stages prior to the appearance of extracellular amyloid aggregates (amyloid plaques and senile plaques), using autopsied human brains with MCI and AD, as well as AD model mice (Tanaka et al., Nature Commun 2020). The second paper describes the clustering of autolysosome-filled cell membrane protrusions, with amyloid present at their center within the cell membrane (Lee et al., Nature Neurosci 2022). The third paper reports that axonal spheroids surrounding early-stage amyloid are filled with endolysosomes positive for the AD genetic risk factor PLD3, and that these spheroids inhibit neurotransmission (Yuan et al., Nature 2022). These neuropathological changes are thought to represent the same morphological entity (Okazawa et al, Alzforum 2022). The first paper is the result of research by the presenter’s group, and will focus on the details of this paper, including the process leading to the discovery of the “ultra-early molecular pathology” and the related HMGB1 antibody treatment developed, along with its relationship to LLPS.

 

The second topic is the mechanism by which microglia mediate tau protein to induce brain inflammation. Recently, it has been reported that the polyglutamine disease-related molecule PQBP1 recognizes HIV capsid proteins or nucleic acids in innate immune cells such as dendritic cells, triggering an inflammatory response to eliminate the AIDS virus (Yoh et al., Cell 2015; Yoh et al., Mol Cell 2022). Meanwhile, PQBP1 is an intrinsically disordered protein (IDP), and it has been previously known to interact with disease-modifying proteins, such as Ataxin-1 or Huntingtin, which are also IDPs, in the formation of LLPS (Okazawa et al., Neuron 2002; Busch et al, JBC 2003). The relationship between tau and PQBP1 in microglia, a type of innate immune cell in the brain, was therefore investigated, and it was shown that tau activates the cGAS-STING system through binding with PQBP1, causing inflammation in the brain (Jin et al, Nature Commun 2021).

 

Furthermore, YAP and the cGAS-STING system are closely related (Sladitschek-Martens et al, Nature 2022), and I will discuss the relationship between the two pathologies and introduce research progress toward elucidating the ultra-early pathology.