A study published in the American Journal of Human Genetics by researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital provides solutions to the pressing need to identify factors that influence Alzheimer's disease (AD) risk or resistance while providing an avenue to explore potential biological markers and therapeutic targets.
The researchers integrated computational and functional approaches that enabled them to identify not only specific genes whose alterations predicted increased AD risk in humans and behavioral impairments in AD fruit fly models but also showed that reversing the gene changes has a neuroprotective effect in living organisms.
"Alzheimer's disease affects more than 50 million people worldwide and although researchers have learned a great deal about it over the years, its causes are still not fully understood and effective therapies are not yet available," said corresponding author Dr. Juan Botas, professor of molecular and human genetics and molecular and cellular biology at Baylor. Botas also is the director of the High-Throughput Behavioral Screening Core at the Duncan NRI.
Although extensive genome-wide studies have uncovered hundreds of genes potentially associated with the disease, assessing the roles these genes play in AD is necessary to distinguish those that confer risk for the condition from uninvolved bystanders.
"We addressed this issue by first integrating published genome-wide association data with multiple computational approaches to identify genes likely involved in AD," said co-first author Morgan C. Stephens, a graduate student in the Botas lab. "We then tested those computational predictions experimentally in the lab."
The researchers systematically perturbed AD candidate genes identified from their computational analyses and assessed their potential to modulate neuronal dysfunction and hallmark AD-related cellular alterations, such as neuropathology or accumulation of tau protein, in living organisms.
"We worked with fruit fly models of the condition to assess whether these altered genes drove neuronal dysfunction leading to motor impairments. Importantly, we also investigated whether reversing the activity of those altered genes would also reverse the motor alterations in flies and tau or beta-amyloid protein accumulation in cells," Botas said.
The computational analyses revealed 123 candidate genes for AD risk and the team confirmed that the expression of many of them is altered in human AD and correlates with the accumulation of tau or beta-amyloid protein in brain cells affected by the condition. Evaluation of 60 of these gene candidates available in fruit fly models pointed at 46 that modulated neuronal dysfunction in one or both fly models. The altered expression of 18 of these genes predicted the increase of AD risk in humans.
Importantly, reversing the alterations in 11 of these genes protected fruit flies from damage to their nervous system.
"In the list of final candidates, MTCH2 turned up to be at the top on the functional studies," Stephens said.
"MTCH2 expression is downregulated in human AD brain samples, and reducing its function in flies aggravates motor dysfunction. It was very exciting to find that restoring MTCH2 expression in flies reversed motor dysfunction and reduced tau accumulation in human neural progenitor cells in the lab."
"Our findings support further exploration of MTCH2 for therapeutic purposes and highlight the value of a combined computational and experimental approach to uncover main genetic players in Alzheimer's disease and other neurodegenerative conditions," Botas said.
Other contributors to this work include co-first author Jiayang Li, as well as Megan Mair, Justin Moore, Katy Zhu, Akash Tarkunde, Bismark Amoh, Alma M. Perez, Arya Bhakare, Fangfei Guo, Joshua M. Shulman and Ismael Al-Ramahi. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Baylor's Center for Alzheimer's and Neurodegenerative Disease.
This work was supported by NIH grants U01AG072439, R01AG074009 and F31NS129062.
