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New Drug Targets Classic Signposts of Alzheimer’s Disease

May Solve Two Problems at Once

In Alzheimer’s disease, amyloid beta solidifies into senile plaques, which congregate in the extracellular spaces of nerve tissue, while tau protein creates tangled forms crowding the bodies of neurons. Those plaques and tangles, considered hallmarks of Alzheimer’s, have been the objects of fierce debate, sustained research, and many billions of dollars in drug development. Yet therapeutic efforts have met with dispiriting failure. 

But a new drug, DYR219, developed by Arizona State University researchers, may solve two issues at once, by targeting both plaques and tangles. Further, DYR219's activity can occur early in the disease, before the formation of these pathologies, offering a better chance of stopping the disease’s progression. “We showed a robust and significant delay in the onset of amyloid and tau pathology,” said Travis Dunckley, a researcher at the ASU-Banner Neurodegenerative Disease Research Center and study author.

DYR219 inhibits DYRK1, a kinase believed to be key in the formation of plaques and tangles. It is vital to the brain during early embryonic development, where it is involved in a host of processes, including signaling pathways linked with cell growth and proliferation, the differentiation of cells into mature neurons, and the formation of dendritic spines essential for the transmission of nerve impulses. 

In the mature brain, however, DYRK1’s activities can turn hostile, initiating pathologies associated with Alzheimer’s, dementia with Lewy bodies, and Parkinson’s disease. The dysfunction of DYRK1 is also a central feature of Down syndrome, and people with this disorder are highly prone to developing Alzheimer’s early in life, often in their 40s or 50s.

The DYRK1 kinase carries out its harmful role in the brain through a process known as phosphorylation. When DYRK1 encounters an amyloid precursor protein (APP), it attaches a cluster of oxygen and phosphorus atoms, known as a phosphate group. DYRK1 also phosphorylates tau.

Too much phosphorylation of these critical proteins can have disastrous effects in the brain. The hyperphosphorylation of APP is believed to increase the formation of amyloid plaques, while tau hyperphosphorylation leads to neurofibrillary tangles.

The need for an effective Alzheimer’s disease therapy could not be more acute. Dementia currently affects nearly 50 million people, striking a new victim somewhere in the world every three seconds. The majority develop Alzheimer’s disease, the most common form of dementia. Barring major advances in treatment, the number of cases is projected to skyrocket to 131.5 million by mid-century.

On a more hopeful note, because Alzheimer’s is primarily a disease of old age, it has been estimated that a therapy capable of delaying the onset by just five years would cut the number of cases globally by half.

Source: Arizona State University, August 14, 2019

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