Redefining, Simplifying the Complexities of Alzheimer Disease and Amyloid Cascade: Ralph Nixon, MD, PhD

WATCH TIME: 4 minutes

"We have evidence that when you reverse the acidification defect, you can substantially rescue this whole subsequent phenomenon. Again, that speaks to the strong validation that this is at the top of the food chain in terms of targets. We think successful targets."

Recently published research in Nature Neuroscience using Alzheimer disease (AD) mouse models challenged the way traditional drug development has viewed targeting the core problems of the disease. For years, the community believed that plaques containing amyloid-ß built outside of cells was the first critical step toward brain damage in AD. Now, in the new findings, investigators observed early-appearing deficiencies of lysosomal vATPase activity, autophagy dysfunction in vulnerable neuron populations, and accumulation of amyloid precursor protein (APP)-ßCTF and amyloid-ß selectively within poorly acidified autolysosomes well before extracellular amyloid-ß deposition.

Led by Ralph Nixon, MD, PhD, the study also identified a unique autophagic stress response in more compromised neurons characterized by fulminant proliferation of autophagic vacuoles within perikaryal and formulation of large membrane blebs packed with amyloid-ß/APP-ßCTF-filled Avs. The strongly fluorescent petal-like blebs surrounding a DAPI-positive fluorescent nucleus generated flower-like profiles Nixon and his colleagues termed PANTHOS (poisonous flower). There, using several imaging and histochemical techniques, established quantitatively that PANTHOS neurons are the origin of the vast majority of senile plaques in AD mouse models.

The findings could have significant impact on drug development and the way the community views the root causes of AD, Nixon said; however, he believes there needs additional validation before the community will be ready to throw their support. Nixon, a professor of psychiatry and cell biology at NYU Langone, sat down to discuss the next steps in expanding on these findings, as well as whether they simplify or complicate what we know about the disease.

REFERENCE
1. Lee JH, Yang DS, Goulbourne CN, et al. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aß in neurons, yielding senile plaques. Nature. 2022;25:688-701. doi:10.1038/s41593-022-01084-8