Researchers have identified new molecular mechanisms driving late-onset Alzheimer's Disease (LOAD), as well as a promising therapeutic candidate for treatment, according to a study in the journal Neuron. LOAD is the most prevalent form of dementia among people over age 65, a progressive and irreversible brain disorder affecting more than 5.5 million people in the U.S., and the sixth leading cause of death.
"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," said the lead author. "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."
Previous genetic and genome-wide association studies (GWAS) have identified some genetic mutations associated with LOAD, but the causal variants of the disease have remained uncharacterized. To explore the molecular mechanisms driving the pathogenesis of LOAD, the team performed an integrative network biology analysis of a whole genome and RNA sequencing dataset from multiple cortical brain regions of hundreds of donors, both healthy and with LOAD. This work revealed thousands of molecular changes and uncovered numerous neuron-specific gene subnetworks dysregulated in LOAD.
From that investigation researchers predicted that ATP6V1A, a protein-coding gene, plays a major role in a critical signaling pathway in the brain, and that its deficit could be traced to LOAD. That linkage was evaluated using two methods: a CRISPR-based technique to manipulate ATP6V1A levels in donor-matched brain cells in vitro, and in RNAi-based knockdown in transgenic Drosophila models, meaning that genetic material is artificially introduced into fly models and specific genes are effectively silenced to study the effects. Indeed, the knockdown of ATP6V1A worsened LOAD-related neurodegeneration in both models.
Just as significantly, researchers predicted that a drug compound, NCH-51, could normalize the dysregulated genes in LOAD, including ATP6V1A, and demonstrated that NCH-51 dramatically improved the neuronal and neurodegenerative effects of the ATP6V1A deficit in both model systems. Specifically, the CRISPR-based experiment using human induced pluripotent stem cells (hiPSC) demonstrated that repression of ATP6V1A, particularly in combination with β-amyloid -- a key neuropathological hallmark of AD -- dramatically impacted neuronal function. "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," observed a co-author of the study.
The Drosophila experiments were also revealing, demonstrating that ATP6V1A deficit exacerbated both β-amyloid-mediated toxicity and tau-mediated axon degeneration. "This finding suggests that ATP6V1A may have broad neuroprotective effects and serve as a potential therapeutic target for other tau-related neurodegenerative diseases," says the senior author of the study.
As the lead points out, the groundbreaking research could have significance beyond just LOAD. "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."
https://www.mountsinai.org/about/newsroom/2020/potential-new-therapies-for-alzheimers-disease-are-revealed-through-network-modeling-of-its-complex-molecular-interactions-pr
https://www.cell.com/neuron/fulltext/S0896-6273(20)30861-8
Molecular Mechanism and Potential Therapeutics for Alzheimer's Disease Using Network Modeling
- 1,149 views
- Added
Edited
Latest News
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Other Top Stories
Cholesterol reduction in monkeys by gene editing!
Read more
Addictive behavior gene identified!
Read more
Why baby's sex may influence risk of pregnancy-related complicatations
Read more
Is sleep an antioxidant?
Read more
Memory identity is stored in specific synapses
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Selenium, diabetes, and the…
By newseditor
Posted 23 Apr
Long-term neuropsychologica…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar