Alzheimer’s disease (AD) arises from molecular events that scientists are piecing together to discern an overall story, parts of which are well known, others less so. Some of the lesser-known epigenetic events in the Alzheimer’s story have just been filled in by scientists based at the Van Andel Research Institute (VARI). What’s more, these epigenetic events, which occur early in Alzheimer’s, appear to fit well with what we know about the disease’s progression to its most devastating biological features.

The new findings center on genetic “volume dials” called enhancers, which turn the activity of genes up or down based on influences such as aging and environmental factors. By taking a comprehensive look at enhancers in brain cells of people at varying stages of Alzheimer’s and comparing them to the cells of healthy people, the VARI scientists found that in Alzheimer’s, the loss of epigenetic marks is accelerated. Consequently, there is a loss of gene repression, such that the affected brain cells act older than they are, leaving them vulnerable to disease.

By over-activating a suite of genes involved in Alzheimer’s pathology, the dysregulated enhancers spur the formation of plaques and tangles and reactivate the cell cycle in fully formed cells.

“In adults, brain cells typically are done dividing. When enhancers reactivate cell division, it’s incredibly damaging,” said Viviane Labrie, PhD, an assistant professor at VARI. “The enhancer changes we found also encourage the development of plaques, which act as gasoline for the spread of toxic tangles, propagating them through the brain like wildfire. Taken together, enhancer abnormalities that promote plaques, tangles, and cell cycle reactivation appear to be paving the way for brain cell death in Alzheimer’s disease.”

Labrie is the senior author of a paper (“Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms”) that appeared May 21 in Nature Communications. The paper describes how the VARI team identified 1224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in Alzheimer’s disease neurons.

“Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons,” the article’s authors wrote. “Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.”

The new findings unify longstanding theories behind the disease’s origins into one cohesive narrative that explains how healthy cells become sick and gives scientists new avenues for screening compounds designed to slow or stop disease progression, something existing medications cannot do.

Based on their findings and those of other researchers, the VARI team proposes the following model:

  • Hypomethylation of enhancers in DSCAML1 activates BACE1 to induce the formation and progression of both Aβ plaques and neurofibrillary tangle pathology in AD.
  • Interaction of DSCAML1 enhancers with their target BACE1 promoter leads to overproduction of Aβ peptides, which will eventually form plaques.
  • Aβ peptides, in turn, engage the hypomethylation of enhancers affecting neurogenesis and cell cycle genes, which are already primed for activation due to the normative loss of CpH methylation marks with aging.
  • Reactivation of cell cycle genes facilitates tau hyperphosphorylation, and along with Aβ plaques, leads to the formation and spread of tangle pathology, resulting in neuronal death and AD cognitive symptoms.

“We now have a better understanding of the molecular factors that lead to Alzheimer’s disease, which we can leverage to develop improved and desperately needed treatment and prevention strategies,” Labrie asserted. “Alzheimer’s is a major growing public health problem around the world. We need better options for patients, and we need them soon.”

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