Potential new avenues for early intervention in Alzheimer’s

alzheimer's

A research team led by Professor Wim Annaert (KU Leuven/VIB) has shed new light on the role of different enzymes in the development of Alzheimer’s disease. Their findings may offer new perspectives in the search for a treatment.

Alzheimer’s disease is characterised by the accumulation of short protein fragments between nerve cells in the brain. These protein fragments are created by gamma secretases, enzymes that cleave proteins into smaller pieces. One of the produced fragments is amyloid beta, which aggregates to form amyloid plaques. These plaques disrupt the communication between brain cells, and their accumulation causes the gradual degeneration of neural networks.

“We’ve known for twenty years that gamma secretases are involved in the development of Alzheimer’s disease,” says Professor Wim Annaert. “But because too little is known about the precise function, structure, and functioning of these secretases, there’s no treatment that specifically targets these enzymes.”

Researcher Ragna Sannerud (KU Leuven / VIB) and her colleagues have now shown for the first time that two different types of gamma secretases are active in different parts of the cell.

Professor Annaert: “The gamma secretases with the protein presenilin2 are only active in the parts of the cell that break down its waste products. This type of secretases mostly produce intracellular amyloid beta protein (Aβ), including its most harmful forms.”

Unlike the Aβ that is released from cells, intracellular Aβ is only present in fairly small amounts. Therefore, its relevance to the development of Alzheimer’s disease has often been overlooked. Unjustly so, according to Professor Annaert: “Accumulation of intracellular Aβ is one of the earliest signs of Alzheimer’s, evident even before the disease manifests.”

“Our discovery shows that selectively blocking presenilin2-γ-secretase is a possible therapeutic pathway. It could enable us to intervene early – when disease progression might still be halted or even reversed – without disrupting other important biological processes.”

The findings are based on cell cultures, but they will be used to develop new mouse models for research into the onset of Alzheimer’s. These models could then be the starting point for the development of new therapies.

Click here to read the study in Cell