Alzheimer’s disease: an alternative hypothesis

image: Human hippocampal brain section of a patient with Alzheimer’s disease showing amyloid precursor protein (green) clustering around amyloid plaques (purple and red).
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Credit: © Gaël Barthet

New research published today in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association may explain why neurons fail to communicate effectively in people with Alzheimer’s disease (AD). The study conducted by researchers from Christophe Mulle’s laboratory at the Interdisciplinary Institute of Neurosciences in Bordeaux1 opens a new avenue of research to establish the molecular mechanism responsible for AD.

Despite intense efforts in clinical research, there is no treatment to cure or even slow the progression of AD. Current clinical interventions are generally based on the “amyloid cascade” hypothesis, postulating that neurodegeneration in AD is caused by the abnormal accumulation of amyloid plaques in the brain. However, these interventions have failed to demonstrate clinical efficacy. Recently, the European Medicines Agency failed to approve a controversial new drug for AD that targets plaques, concluding that the benefits do not outweigh the risks. The decision leaves around 8 million people with dementia in the EU without treatment options, underscoring the urgent need for an alternative target for Alzheimer’s disease research.

The new study reveals that the amyloid peptide that makes up plaques isn’t the only offender accumulating in the human brain with Alzheimer’s disease. Its precursor, amyloid precursor protein (APP), has been shown to surround amyloid plaques in intense microscopic staining.

“Remarkably, our research revealed that areas of the brain where APP accumulates contain abnormal amounts of proteins that are essential for communication between neurons,” lead author Dr Gael Barthet said today. now director of neuroscience at the Wyss Center.

Communication between neurons occurs at junctions called synapses where neurotransmitters released by a pre-synaptic neuron cross the junction to activate a post-synaptic neuron.

“What we found fascinating was that APP accumulated with excess presynaptic proteins while postsynaptic proteins were depleted, indicating severe impairment of neuronal communication at these sites,” said the Dr. Tomas Jorda, lead author of the article and post-doctoral research associate in neurobiology at the University of Geneva.

“The new findings introduce a new direction that we need to explore using our innovative, multiscale, multimodal approach at the Center,” said Dr. Richie Kohman, Scientific Director of the Wyss Center.

The Wyss Center’s translational research in neurodegenerative diseases uses novel molecular tagging techniques combined with advanced microscopy and data analysis tools to examine specific neuronal populations, synaptic markers, and single-cell transcriptomics in the human brain. These innovative imaging approaches allow the study of the human brain in large sections or even in whole 3D samples. The Wyss Center uses this pipeline to study the molecular mechanisms involved in neurological and psychiatric disorders, establish early biomarkers and identify new therapeutic targets.

The article, “APP accumulates with presynaptic proteins around amyloid plaques: a role for presynaptic mechanisms in Alzheimer’s disease?” is published in Alzheimer & Dementia 2022 DOI: 10.1002/alz.12546


Search contacts:

Gael Barthet

Director of Neurosciences

[email protected]

+41 58 201 03 67

Wyss Center for Bio and Neuroengineering

Chemin des Mines 9, 1202 Geneva, Switzerland

1 Christophe Mulle
Research director at CNRS

[email protected]

Team ‘Synaptic circuits of memory’
Interdisciplinary Institute of Neurosciences, CNRS
University of Bordeaux

Bordeaux France

About the Wyss Center for Bio and Neuroengineering, Geneva, Switzerland

The Wyss Center is an independent, nonprofit research and development organization that advances our understanding of the brain to achieve therapies and improve lives.

Wyss Center staff, along with the Center’s academic, clinical, and industrial collaborators, pursue innovations and new approaches in neurobiology, neuroimaging, and neurotechnology.

Advances from the Wyss Center reveal unique insights into the mechanisms underlying brain dynamics and disease treatment to accelerate the development of devices and therapies for unmet medical needs.

The Wyss Center was established through a generous gift from Swiss entrepreneur and philanthropist Hansjörg Wyss in 2014. Additional resources from funding agencies and other sources help the Wyss Center accelerate its mission.

Media contact

Wyss Center

Jo Bowler, Media and Public Relations Manager

+41 (0) 58 201 03 09

[email protected]

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