The results of a study in mice by scientists at NYU Grossman School of Medicine and at the Nathan Kline Institute suggest that a breakdown in how brain cells rid themselves of waste precedes the build-up of debris-filled plaques known to occur in Alzheimer’s disease (AD). The research, in mice bred to develop AD, traced the root dysfunction to the brain cells’ lysosomes. The findings challenge the amyloid cascade hypothesis proposing that plaques containing amyloid beta (Aß) build up outside of cells as a crucial first step toward the brain damage observed in AD. Instead, the new results argue that neuronal damage characteristic of AD takes root inside cells and well before the thread-like amyloid plaques fully form and clump together in the brain.

The study findings could have implications for the future focus of AD therapeutics, the team suggests. “This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why so many experimental therapies designed to remove amyloid plaques have failed to stop disease progression, because the brain cells are already crippled before the plaques fully form outside the cell,” said study senior investigator Ralph Nixon, MD, PhD, a professor in the department of psychiatry and the department of cell biology at NYU Langone, as well as director of the Center for Dementia Research at Nathan Kline. “Our research suggests that future treatments should focus on reversing the lysosomal dysfunction and rebalancing acid levels inside the brain’s neurons.”

Lysosomes are small, enzyme-filled sacs that are found in every cell, and play a role in the routine breakdown, removal, and recycling of metabolic waste from everyday cell reactions, as well as from disease. Lysosomes are also key to breaking down and disposing of a cell’s own parts when the cell naturally dies. “Autophagy is the principal pathway for lysosomal degradation,” the authors further wrote, “maintaining cellular homeostasis by constitutively turning over obsolete proteins and organelles.” Autophagy can also be further induced by cell stress or disease, to help eliminate abnormal proteins, aggregates, or damaged cell structures. There are several mechanisms of autophagy by which cells can collect and deliver waste material to these lysosomes, the team continued.

National Institute on Aging figures indicate that more than six million people in the United States—most of them aged 65 years or over—have AD-related dementia. Autophagy is “markedly impaired” in AD, the team further noted. As part of their newly reported work, the researchers tracked decreasing acid activity inside intact mouse cell lysosomes as the cells became injured through AD. Imaging tests to track cellular waste removal, developed at NYU Langone Health and Nathan Kline, showed that certain brain cell lysosomes became enlarged as they fused with autophagic vacuoles filled with waste that had failed to be broken down. These autophagic vacuoles also contained earlier forms of amyloid beta.

In neurons that are the most heavily damaged and destined for early death as a result, the vacuoles pooled together in “flower-like” patterns, bulging out from the cells’ outer membranes and massing around each cell’s center, or nucleus. “In more compromised yet still intact neurons, profuse Aß-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes,” the authors wrote. “This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains.”

Three images, as seen by fluorescent microscopy, show flower-like formations (at decreasing resolution) of autophagic vacuoles in neurons of Alzheimer’s disease mice. [Courtesy of Springer-Nature Publishing]

 

The studies involving five different mouse models showed that accumulations of amyloid beta formed filaments inside the cell, another hallmark of AD. Indeed, researchers observed almost-fully formed plaques inside some damaged neurons. “Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar β-amyloid accumulates intraluminally,” they noted.

Study lead investigator Ju-Hyun Lee, PhD, a research assistant professor in the department of psychiatry and NYU Langone Health and research scientist at Nathan Kline, said the team’s study “for the first time sources neuronal damage observed in Alzheimer’s disease to problems inside brain cells’ lysosomes where amyloid beta first appears … Previously, the working hypothesis mostly attributed the damage observed in AD to what came after amyloid build up outside of brain cells, not before and from within neurons.”

The authors further commented, “β-amyloid plaque formation in AD has commonly been considered to originate from extracellular deposition of β-amyloid derived from secreted Aβ, which then triggers secondary neuritic dystrophy and neuronal cell death … By contrast, our evidence in diverse AD models supports the opposite sequence—namely, extracellular plaques mainly evolve from intraneuronal build-up of β-amyloid within membrane tubules, forming a centralized amyloid ‘core’ within single intact PANTHOS neurons that subsequently degenerate to give rise to the classical senile plaque … we establish quantitatively that PANTHOS neurons are the origin of the vast majority of senile plaques in AD mouse models, thus prompting a reconsideration of the conventionally accepted sequence of events in plaque formation in AD.”

Researchers say they are now working on experimental therapies to treat the lysosomal problems observed in their studies. A recent study (published in April in Science Advances) by the NYU Langone team sourced one cause of the cell’s waste disposal problems to a gene called PSEN1. The gene has long been known to cause AD, but its additional role in causing the illness (through lysosomal dysfunction) is only now becoming clear. Their recent work also showed that the neuronal damage in a PSEN1 mouse model of AD could be reversed by restoring proper acid levels in lysosomes.

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