Skip to main content

Or 34,00 After 66% tax deduction

I make a monthly donation I make an IFI donation
Research, science & health

New insights on a major protein involved in Alzheimer’s disease

Published on: 16/12/2020 Reading time: 1 min
image

New study conducted by Irini Kessissoglou in the “Brain development” team headed by Bassem Hassan at Paris Brain Institute reveals new functions for the Amyloid Precursor Protein (APP) homologue in drosophila. Results are published in PLOS Biology.

The amyloid precursor protein (APP) is an essential protein, best known for its involvement in the pathway at the origin of amyloid beta, the component of the main lesion in Alzheimer’s disease (AD), the amyloid plaques. Mutations in the APP gene are linked with early-onset familial cases of AD. However, the physiological role of APP in adult brain function and whether there is any link between this normal role and defects seen in AD remains unclear. To address this issue, Kessissoglou et al. investigated the function of this protein in the fruit fly, Drosophila melanogaster, a model organism often used in biomedical research which possesses a homologue of APP, called APPL (Amyloid precursor protein like).

Neurons, like all cells, possess a system called the endolysosomal recycling and degradation pathway for separating, recycling and, when necessary, trashing its proteins. This system guarantees protein and organelles balance neurons and it has been shown to be defective in human neurons with AD patient mutations, suggesting that APP may be be important for this process under normal conditions.

Using Drosophila model of APPL loss of function, the authors explored the molecular and cellular mechanisms underlying the brain homeostasis, which can be defined as the physiological processes necessary to maintain brain health and restoring balance in case of injury or diseases.

They identified a pathway crucial for adult brain homeostasis involving APPL. Indeed, APPL loss of function leads in a disruption of the endolysosomal function in neurons followed by cell death. The dead neuronal cell, which are significantly increased with the loss of APPL, accumulate in the brain at early age. Moreover, not only did flies lacking APPL have a shorter lifespan and neurodegeneration by 30 days old (a middle-old age at the scale of a Drosophila), their brain also showed signs of dysfunctional homeostasis as early as 7 days old.

One key point of the study is the evidence that the extracellular domain of APPL secreted by neurons interacts with glial cells to regulate their endolysosomal pathway and enable the clearance of neuronal debris. Glial cells are key elements of brain homeostasis as they are involved in immune response, providing nutrients to neurons and clearance of cellular wastes. Overall, this suggest that APPL is part of a neuro-glial signaling system responsible for monitoring brain health.

The results of this study bring new insights on the role of APP in a physiological context and highlight its importance for adult brain homeostasis. The findings regarding the consequences of the loss of APP suggests a strong link between its physiological functions and the defects observed in familial cases of Alzheimer’s disease. The early effects observed in flies lacking APPL support the idea of long-term modifications in the brain occurring before the onset of clinical symptoms, fostering new research on early endosomes and neuro-glial interactions in this disease.

Sources

https://pubmed.ncbi.nlm.nih.gov/33290404/
Kessissoglou IA, Langui D, Hasan A, Maral M, Dutta SB, Hiesinger PR, Hassan BA.PLoS Biol. 2020 Dec 8

Our news on the subject

Interneurones. Crédit : UCLA Broad Stem Cell Research Center.
Stimulating specific neurons in the striatum stops compulsive behaviour
What if we could resist compulsions? These irrational behaviours, particularly common in obsessive-compulsive disorder (OCD), are hard to suppress. At Paris Brain Institute, Éric Burguière's team shows that we can anticipate them and block them ...
09.10.2024 Research, science & health
Les nerfs moteurs présents dans la moelle épinière se projettent vers la périphérie, où ils entrent en contact avec les muscles, formant des connexions appelées jonctions neuromusculaires. Crédit : James N. Sleigh.
Ultrasound show unexpected effects on motor neuron disease
Over the past fifteen years, neurosurgeons have been perfecting a fascinating technique: using ultrasound to temporarily open the blood-brain barrier to facilitate the action of therapeutic molecules in the central nervous system. At Paris Brain ...
09.05.2024 Research, science & health
Un neurone
Rett syndrome: a new gene therapy on the way
Gene therapy could be our best chance of treating Rett syndrome, a neurological disorder that causes severe intellectual and motor impairments. At Paris Brain Institute, Françoise Piguet and her colleagues have looked closely at brain cholesterol ...
07.16.2024 Research, science & health
Lésions d’un patient à l’inclusion dans le protocole (M0) disparues après 2 ans de traitement à la Leriglitazone (M24)
The dual effect of leriglitazone in X-linked Adrenoleukodystrophy (X-ALD)
In 2023, the team led by Professor Fanny Mochel (AP-HP, Sorbonne University), a Paris brain Institute researcher, showed that daily dose of leriglitazone slow down the progression of myelopathy in patients with X-linked adrenoleukodystrophy, and ...
06.28.2024 Research, science & health
Une tête de statue de l'île de Pâques sur laquelle sont posées des éléctrodes
A multimodal approach to better predict recovery in patients with disorders of consciousness
When a patient is admitted to intensive care due to a disorder of consciousness—such as a coma—establishing their neurological prognosis is a crucial yet challenging task. To reduce the uncertainty that precedes the medical decision, a group of ...
05.30.2024 Research, science & health
Population de bactéries commensales (en rouge) dans un intestin grêle de souris. Crédit : University of Chicago
The composition of the gut microbiota could influence decision-making
The way we make decisions in a social context can be explained by psychological, social, and political factors. But what if other forces were at work? Hilke Plassmann and her colleagues from the Paris Brain Institute and the University of Bonn show ...
05.16.2024 Research, science & health
See all our news