Glial Cells Play Key Role in Alzheimer’s Development

Summary: New research reveals that glial cells, specifically oligodendrocytes, produce amyloid beta, a protein linked to Alzheimer’s disease, challenging the long-held belief that neurons are the sole contributors.

This discovery opens new possibilities for therapies aimed at preventing plaque formation in the brain. Targeting both neurons and glial cells could slow the disease’s progression by inhibiting amyloid beta production before plaques form.

Key facts

  • Glial cells, not just neurons, produce amyloid beta involved in Alzheimer’s.
  • Blocking amyloid production in glial cells reduced brain plaques by 30%.
  • This finding may lead to earlier, more effective Alzheimer’s therapies.

Source: Max Planck Institute

Memory loss, confusion, speech problems – Alzheimer’s disease is the most common cause of dementia, affecting about 35 million people worldwide, and the number is growing.

The protein amyloid beta, which occurs naturally in the brain, plays a central role in the disease: It accumulates in patients in insoluble clumps that form plaques between neurons in the brain, damaging them.

This shows neurons.
Do glial cells play an even greater role in the disease than previously thought? Credit: Neuroscience News

Researchers at the Max Planck Institute (MPI) for Multidisciplinary Sciences have now shown that, in addition to neurons, special glial cells in the brain also produce amyloid beta. This finding could open up new avenues for future therapies.

There is no cure for Alzheimer’s disease. However, there are therapeutic approaches to reduce the amyloid plaques in the brain. That can slow down the progression of the disease, but it cannot reverse or stop it.

“Until now, neurons were thought to be the main producers of amyloid beta and have been the main target for new drugs,” explains Klaus-Armin Nave, Director at the MPI for Multidisciplinary Sciences.

Results from his Department of Neurogenetics have now shown: In addition to neurons, special glial cells – called oligodendrocytes – play an important role in plaque formation.

“One of the tasks of oligodendrocytes is to form myelin – an insulating layer – and wrap it around the nerve fibers to speed up signal transmission,” explains Andrew Octavian Sasmita, one of the first authors of the study now published in Nature Neuroscience and a former PhD student in Nave’s team.

In a previous study, the Göttingen researchers had already discovered that defective myelin of oligodendrocytes exacerbates Alzheimer’s disease. Do glial cells play an even greater role in the disease than previously thought?

“We have now shown that although neurons are the main producers of amyloid beta, oligodendrocytes also produce a significant amount of the protein which is incorporated into plaques,” says Sasmita.

A research group led by Marc Aurel Busche of the University College London (England) recently came to similar conclusions.

Preventing plaque formation

The cells of the nervous system produce amyloid beta by cleaving a larger precursor molecule with help of an enzyme called BACE1. For their experiments, the researchers specifically knocked out BACE1 in the neurons and oligodendrocytes of mice.

They then used 3D light-sheet microscopy to study plaque formation throughout the brain, providing a complete picture of amyloid plaques in all brain regions.

“Oligodendrocytes lacking BACE1 developed about 30 percent fewer plaques. Knocking out the BACE1 gene in neurons reduced plaque formation by over 95 percent,” says Constanze Depp, also a first author of the study and a former PhD student in Nave’s department.

The scientists also found out: “Plaque deposits only form when a certain amount of neuronal amyloid beta is present. The oligodendrocytes then contribute to these plaques.”

This threshold could be useful for Alzheimer’s therapies.

“If we can successfully inhibit BACE1 before this threshold is reached, the plaques might form later,” Nave emphasizes.

That could help to slow down the progression of Alzheimer’s disease at an early stage.

About this Alzheimer’s disease research news

Author: Celina Böker
Source: Max Planck Institute
Contact: Celina Böker – Max Planck Institute
Image: The image is credited to Neuroscience News

Original Research: Open access.
Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice” by Klaus-Armin Nave et al. Nature Neuroscience


Abstract

Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice

Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer’s disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs).

By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that OLs and neurons contribute to Aβ plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aβ.

Ultimately, our findings are relevant for AD prevention and therapeutic strategies.

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