Researchers identify promising treatments for late-onset Alzheimer’s disease

Scientists from The Mount Sinai Hospital and the National Center for Geriatrics and Gerontology based in Japan have recently discovered novel molecular mechanisms that drive late-onset Alzheimer’s disease (LOAD).

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According to a new study published in the Neuron journal, these molecular mechanisms could also serve as a potential therapeutic candidate for treating this medical condition.

LOAD—the most widespread form of dementia that affects individuals aged over 65—is an irreversible and progressive brain disorder. This disease affects over 5.5 million people in the United States and is the sixth leading cause of mortality.

Our study advances the understanding of LOAD pathogenesis by revealing not only its global structures, but detailed circuits of complex molecular interactions and regulations in key brain regions affected by LOAD.”

Bin Zhang, PhD, Study Lead Author and Professor of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai

Zhang, who is also the Director of the Center for Transformative Disease Modeling, added that “The network models we created serve as a blueprint for identifying novel therapeutic targets that respond directly to the urgent need for new ways to prevent, treat, and delay the onset of LOAD.”

Earlier genetic and genome-wide association studies (GWAS) performed by scientists have revealed certain genetic mutations that were linked to LOAD; however, the causal variants of this disorder were not defined to date.

Hence, to investigate the molecular mechanisms that fuel the pathogenesis of LOAD, a research team, headed by the Mount Sinai Hospital, carried out an integrative network biology analysis of RNA sequencing and a whole genome dataset from numerous cortical brain areas of countless numbers of donors—both healthy individuals and those with the LOAD disorder.

The study demonstrated scores of molecular variations and revealed many neuron-specific gene subnetworks that were dysregulated in LOAD.

From that analysis, the investigators were able to estimate that a protein-coding gene, called ATP6V1A, plays a crucial role in a major signaling pathway in the brain, and they learned that the dearth of this specific gene can be traced to LOAD.

The researchers evaluated that association using two techniques—a CRISPR-based method to exploit the levels of the ATP6V1A gene in donor-matched brain cells in vitro, and in RNAi-based knockdown in transgenic Drosophila models. This means that the genetic material is artificially added to fly models and that certain genes are successfully silenced to analyze the effects.

The team found that the knockdown of the ATP6V1A gene indeed worsened the LOAD-associated neurodegeneration in these two models.

More importantly, the researchers estimated that a drug compound, called NCH-51, could normalize the dysregulated genes, including the ATP6V1A gene, in the LOAD disorder, and showed that the NCH-51 compound considerably enhanced the neurodegenerative and neuronal impacts of the ATP6V1A deficit in the two model systems.

In particular, the CRISPR-based experiment utilizing human induced pluripotent stem cells (hiPSC) showed that repression of the ATP6V1A gene, specifically in tandem with a major neuropathological hallmark of AD, called β-amyloid, significantly affected the function of neurons.

The human-based system we created proved to be a promising way to model the mechanisms underlying risk and progression in diseases like LOAD where living tissues are not available.”

Kristen Brennand, PhD, Study Co-Author and Associate Professor, Genetics and Genomic Sciences, The Mount Sinai Hospital

Experiments involving the Drosophila models were equally illuminating, and showed that the deficit of the ATP6V1A gene not only exacerbated β-amyloid-mediated toxicity but also led to the degeneration of the tau-mediated axon.

This finding suggests that ATP6V1A may have broad neuroprotective effects and serve as a potential therapeutic target for other tau-related neurodegenerative diseases.”

Dr Koichi M. Iijima, Head of the Department of Alzheimer’s Disease Research, National Center for Geriatrics and Gerontology

Dr Iijima is also the study’s senior author.

As pointed out by Dr Zhang, the revolutionary study made by The Mount Sinai Hospital and its Japanese associate could have major implications besides the LOAD disorder.

“We’ve created a framework for advanced modeling of complex human diseases in general, and that could well lead to the discovery of molecular mechanisms and the identification of novel targets that are able to deliver transformative new therapeutics,” concluded Dr Zhang.