Researchers connect the dots between cause-effect events in Alzheimer’s disease

A study published in Molecular Psychiatry reveals a path of cause-effect molecular events that can lead to Alzheimer’s disease (AD). Researchers at Baylor College of Medicine, Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and collaborating institutions integrated postmortem human brain gene expression analyses with laboratory fruit fly studies. Their goal was to better understand how typical Alzheimer’s brain changes, such as the formation of amyloid plaques and tau tangles, can lead to neurodegeneration and cognitive decline. Their cross-species approach revealed that some paths seem to aggravate the disease while others may protect against it.

“One important way to investigate the molecular cascade leading to cognitive decline is to study brain gene expression changes from individuals with Alzheimer’s disease when compared with those from healthy brains,” said corresponding author Dr. Joshua Shulman, professor of neurology, neuroscience and molecular and human genetics at Baylor. He also is an investigator and co-director of the Duncan NRI. “The Accelerating Medicines Partnership (AMP)-AD target discovery consortium, which we are a part of, analyzed about 2,000 postmortem brain tissue samples and identified 30 AD-associated gene expression networks. The association with Alzheimer’s was particularly robust for genes involved in immune and synaptic, or neuron communication, regulatory mechanisms.”

An important question remained. Of those gene expression changes, which cause the disease and which are innocent bystanders? 

“Our role in the consortium was to try to answer that question,” Shulman said. “We used the fruit fly as a model system to test hundreds of different genes whose expression was altered in human brains with Alzheimer's disease and try to sort out which genes might play a causal role. We also wanted to know which genes promote versus protect against disease.”

The fruit fly is an ideal laboratory model to answer this question. The AD-associated gene expression networks identified by AMP-AD human brain analyses include between 500 to 5000 genes. “In the fruit fly we can test many different genes in a relatively short time,” Shulman explained. “We manipulate the genes in the fly to resemble the change in human brains and determine which genes enhance or suppress neurodegeneration in the flies or have no effect.”

Shulman and his colleagues studied in the fruit fly 344 genes whose expression was altered in brains with Alzheimer’s disease. These included immune response genes with increased expression in the human condition. When the researchers similarly activated the expression of these genes in flies, they promoted neurodegeneration. This suggests that these genes may play a causal role in the disease and are worth further study.

An unexpected finding emerged when the team was studying genes involved in synaptic regulation. The activity of these genes is reduced in Alzheimer’s brains. “We thought at the beginning that this reduction in activity was a consequence of the death of brain cells that comes with the disease,” Shulman said. “But our experiments with fruit flies showed us something surprising.”

When the researchers silenced the synaptic genes in fruit flies to simulate what occurs in Alzheimer’s brains, they discovered that the flies’ brain cells were instead protected from death. “We conducted a variety of experiments to try to understand this observation,” Shulman said. “Prior published work suggests that brain cells may become abnormally hyperactive in Alzheimer’s disease. Our results suggest that the reduced expression of synaptic genes may in fact represent a compensatory response to the damaging brain cell hyperactivity.”

Taking these and other findings together, the team has proposed a ‘biphasic’ or two-stage model that connects hypothetical cause-effect events leading to Alzheimer’s. Early in the disease, amyloid plaques may trigger an initial increase in synaptic genes that hyperactivate brain cells, contributing to damage. Later, tau tangles appear to reduce the expression of these same genes as a protective response. “However, this human brain response appears to be too little, too late, since ultimately, brain function deteriorates further leading to dementia,” Shulman said.

“Our new understanding of the molecular cascade and gene expression networks causing Alzheimer’s disease pinpoints specific driver genes and pathways worthy of further study as potential therapeutic targets,” Shulman said. 

Other contributors to this work include Pinghan Zhao, Omar El Fadel, Anh Le, Carl Grant Mangleburg, Justin Dhindsa, Timothy Wu, Jinghan Zhao, Meichen Huang, Bismark Amoh, Aditi Sai Marella, Yarong Li, Zhandong Liu, Ismael Al-Ramahi and Juan Botas, all affiliated with Baylor College of Medicine and/or the Duncan NRI. Authors Nicholas T. Seyfried and Allan I. Levey are at Emory University.

This study was supported by National Institutes of Health (NIH) grants (U01AG061357, R01AG057339, RF1AG078660, P30CA125123, P30CA125123, 1S10OD023469), The Florence and William K. McGee, Jr. Family Foundation, Huffington Foundation, the Southern Star Medical Research Foundation, The Effie Marie Caine Endowed Chair for Alzheimer’s Research and CPRIT (grant RP200504). Further support was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH under award numbers P50HD103555 and U54HD083092 and the Duncan NRI. The Religious Orders Study and Rush Memory and Aging Project is supported by P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, and U01AG61356.