PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

New mechanism uncovered in early stages of Alzheimer's disease

APP-CTFs disrupt organellar communication, interfering with cellular homeostasis

New mechanism uncovered in early stages of Alzheimer's disease
2024-04-15
(Press-News.org) Leuven (Belgium), 16 April 2024 – Alzheimer's disease (AD) remains one of the most challenging and prevalent neurodegenerative disorders, affecting millions of individuals worldwide. In a new study published in Developmental Cell, researchers from the lab of Wim Annaert (VIB-KU Leuven) have identified a novel mechanism potentially connected to the early stages of AD. They demonstrated that a fragment of the amyloid precursor protein (APP), called APP-CTF, disrupts communication between cellular compartments crucial for calcium storage and waste disposal, which could be an early event preceding neuronal cell death. These findings, with potential implications for the development of new AD treatments, suggest that preventing APP-CTF accumulation needs to be taken into account to develop more effective treatments.

Alzheimer's disease is characterized by the progressive loss of cognitive function, memory impairment, and behavioral changes. One of the visible features in the brains of people with Alzheimer's disease is the formation of amyloid plaques – clumps of β-amyloid (Aβ) peptides, which are degraded products of amyloid precursor protein (APP). These Aβ-fragments accumulate in neurons early in the disease, even before cognitive decline is observed.

New research, however, suggests that there might even be earlier events happening in the AD brain before plaque formation and that the APP protein plays a role in these early stages. The mechanism behind this remained a mystery until now.

In their latest study, the lab of Wim Annaert at the VIB-KU Leuven Center for Brain & Disease Research identified a mechanism explaining how APP may contribute to these early stages of AD. This discovery could lead to a new direction in AD research and treatment approaches.

Disrupting cellular communication

APP is found in the cell membranes of brain cells. The brain constantly produces new APP molecules while breaking down and removing old ones. This process involves enzymatic scissors, with gamma-secretase being the final one that generates the well-known and well-studied Aβ peptides in AD.

For a long time, it was thought that blocking gamma-secretase would be the logical step to prevent the production of toxic Aβ fragments. However, this leads to the accumulation of their precursor, the APP-C-Terminal Fragments, or APP-CTFs. Now, the researchers have discovered that these fragments are also toxic to neurons. They appear to accumulate between the endoplasmic reticulum (ER), the compartment that is crucial for lipid synthesis and calcium storage, and the lysosomes, the so-called ‘waste bins’ of neurons, which are critical for degrading the cell’s waste products.

“By doing so, APP-CTFs disrupt the delicate balance of calcium within lysosomes," explains Dr. Marine Bretou, first author of the study. "This disruption triggers a cascade of events. The ER can no longer effectively refill lysosomes with calcium, leading to a buildup of cholesterol and a decline in their ability to break down cellular waste. This results in the collapse of the entire endolysosomal system, a crucial pathway for maintaining healthy neurons."

The new study further supports that the APP-CTFs resulting from suppressing gamma-secretase might actually be the culprit behind endolysosomal dysfunction, as observed in the very early stages of AD.

A paradigm shift in understanding the early stages of AD pathogenesis

This research significantly advances our comprehension of the potential causes of disease in the early stages of AD. A remarkable outcome of this study is that these early stages could be caused by another fragment of the same APP molecule rather than Aβ. This has significant implications for the current therapeutic approaches that aim to clear the AD brain from amyloid plaques, as they tend to ignore the toxic effects of other fragments. Other attempts focus on tau proteins or neuroinflammation, which are other hallmarks of AD progression that target later events. However, early intervention is likely the key to stopping or even preventing AD.

"The failure of clinical trials using gamma-secretase inhibitors may be explained by the fact that we were focusing on only one culprit and at a too late stage in the disease," explains Prof. Wim Annaert, lead author of the study. “Our research findings suggest that gamma-secretase modulators, which can help promote clearance of toxic APP-CTFs without blocking the enzyme completely, may be a more relevant target for early intervention in AD. The key might be finding the right balance between APP-CTF clearance and plaque prevention.”

Looking ahead, the scientists are joining efforts with colleagues to develop these modulators based on these novel insights and will continue exploring cellular homeostasis in the early stages of AD.



Publication

Accumulation of APP C-terminal fragments causes endolysosomal dysfunction through the dysregulation of late endosome to lysosome-endoplasmic reticulum contact sites. Bretou, et al. Developmental Cell, 2024. DOI: 10.1016/j.devcel.2024.03.030

The research was funded by Fondation Recherche Alzheimer - Stichting Alzheimer Onderzoek (STOPALZHEIMER.BE), the Alzheimer’s Association, and the FWO Program.

END

[Attachments] See images for this press release:
New mechanism uncovered in early stages of Alzheimer's disease

ELSE PRESS RELEASES FROM THIS DATE:

Elite coaches leaving home as Western countries seek sport success

2024-04-15
Nations battling for Olympic success in a global sporting ‘arms race’ has led to elite coaches migrating to Western countries as they bid to escape antiquated and restrictive coaching regimes in their home countries, reveals a new study funded by the International Olympic Committee’s Olympic Studies Centre. National teams pursuing Olympic gold medals are increasingly recruiting foreign elite coaches from the leading countries, as they try to close the gap between themselves and the top medal-winners in particular ...

Millions of gamers advance biomedical research

Millions of gamers advance biomedical research
2024-04-15
Leveraging gamers and video game technology can dramatically boost scientific research according to a new study published today in Nature Biotechnology. 4.5 million gamers around the world have advanced medical science by helping to reconstruct microbial evolutionary histories using a minigame included inside the critically and commercially successful video game, Borderlands 3. Their playing has led to a significantly refined estimate of the relationships of microbes in the human gut. The results of this collaboration will both substantially advance our knowledge of the microbiome ...

Global North energy outsourcing demands more attention

2024-04-15
Manufacturing nations in the Global North are stockpiling energy and emission problems by outsourcing energy-intensive industrial processes to countries in the Global South, a new study reveals. Global North countries use their advantages in capital and technology to grab a large amount of energy through outsourcing - creating a ‘false decoupling’ of energy consumption from economic growth. But backward production technologies in the Global South tend to result in more energy consumption per unit of output – leading to greater carbon emissions ...

Mayo researchers invented a new class of AI to improve cancer research and treatments

2024-04-15
ROCHESTER, Minnesota — Mayo Clinic researchers recently invented a new class of artificial intelligence (AI) algorithms called hypothesis-driven AI that are a significant departure from traditional AI models which learn solely from data. In a review published in Cancers, the researchers note that this emerging class of AI offers an innovative way to use massive datasets to help discover the complex causes of diseases such as cancer and improve treatment strategies. "This fosters a new era in designing targeted and informed AI algorithms to solve scientific questions, ...

Machine learning could help reveal undiscovered particles within data from the Large Hadron Collider

2024-04-15
Scientists used a neural network, a type of brain-inspired machine learning algorithm, to sift through large volumes of particle collision data. Particle physicists are tasked with mining this massive and growing store of collision data for evidence of undiscovered particles. In particular, they’re searching for particles not included in the Standard Model of particle physics, our current understanding of the universe’s makeup that scientists suspect is incomplete. As part of the ATLAS collaboration, scientists ...

metaphacts and Dimensions launch the Dimensions Knowledge Graph, powered by metaphactory

2024-04-15
Digital Science solutions metaphacts and Dimensions are excited to announce the highly anticipated launch of the Dimensions Knowledge Graph, a large ready-made knowledge graph powering AI solutions in the pharmaceutical and life sciences industries.  The Dimensions Knowledge Graph, powered by metaphactory, is an all-in-one knowledge graph solution, ready-made for easy integration with customers’ data infrastructure and existing internal knowledge graphs. At its core is an explicitly defined and flexible semantic model that can be easily extended to include internal data (which can range from domain expert knowledge or data from internal documents) ...

Parent perceptions of school meals influence student participation in school meal programs

2024-04-15
Philadelphia, April 15, 2024 – Since the implementation of the Healthy, Hunger-Free Kids Act in 2010, school meals in the United States have significantly improved. Several factors have been reported to impact student participation in school meals, including parental perceptions of school breakfast and lunch. A recent research article in the Journal of Nutrition Education and Behavior, published by Elsevier, assessed the association between parent perspectives on the school meal program and student participation. Researcher ...

Hydrogen recombination found to be most plausible explanation for high levels of energy in stellar superflares

2024-04-15
Although their primary purpose is to look for exoplanets, observatories like the Kepler Space Telescope and the Transiting Exoplanet Survey Satellite (TESS) have supplied a vast amount of data on stellar flares, detected with high-precision photometry by broadband filters in the visible light spectrum. The stars are so far away that they appear only as points of light to these telescopes, and the phenomena interpreted as stellar flares are abrupt increases in the brightness of these points. There is also a lack of data in other parts of the electromagnetic spectrum, and most studies of these events focus on irradiated ...

Microplastics make their way from the gut to other organs, UNM researchers find

2024-04-15
It’s happening every day. From our water, our food and even the air we breathe, tiny plastic particles are finding their way into many parts of our body. But what happens once those particles are inside? What do they do to our digestive system? In a recent paper published in the journal Environmental Health Perspectives, University of New Mexico researchers found that those tiny particles – microplastics – are having a significant impact on our digestive pathways, making their way from the gut and into the tissues of the kidney, liver and brain. Eliseo Castillo, PhD, an associate professor in the Division of Gastroenterology ...

Unlocking the secrets of forest heights: the role of GEDI LiDAR technology

Unlocking the secrets of forest heights: the role of GEDI LiDAR technology
2024-04-15
A team of researchers has unveiled a novel approach to accurately characterizing tree height composition in forests using the Global Ecosystem Dynamics Investigation (GEDI) Light Detection and Ranging (LiDAR) technology. This study marks a significant advancement in our understanding of forest ecosystems, shedding light on the intricacies of tree height variability and its implications for ecological studies and climate change mitigation efforts. Tree height composition, a vital ecological attribute, plays a significant role in influencing forest ecosystems, impacting biodiversity, carbon ...

LAST 30 PRESS RELEASES:

A third of licensed GPs in England not working in NHS general practice

ChatGPT “thought on the fly” when put through Ancient Greek maths puzzle

Engineers uncover why tiny particles form clusters in turbulent air

GLP-1RA drugs dramatically reduce death and cardiovascular risk in psoriasis patients

Psoriasis linked to increased risk of vision-threatening eye disease, study finds

Reprogramming obesity: New drug from Italian biotech aims to treat the underlying causes of obesity

Type 2 diabetes may accelerate development of multiple chronic diseases, particularly in the early stages, UK Biobank study suggests

Resistance training may improve nerve health, slow aging process, study shows

Common and inexpensive medicine halves the risk of recurrence in patients with colorectal cancer

SwRI-built instruments to monitor, provide advanced warning of space weather events

Breakthrough advances sodium-based battery design

New targeted radiation therapy shows near-complete response in rare sarcoma patients

Does physical frailty contribute to dementia?

Soccer headers and brain health: Study finds changes within folds of the brain

Decoding plants’ language of light

UNC Greensboro study finds ticks carrying Lyme disease moving into western NC

New implant restores blood pressure balance after spinal cord injury

New York City's medical specialist advantage may be an illusion, new NYU Tandon research shows

Could a local anesthetic that doesn’t impair motor function be within reach?

1 in 8 Italian cetacean strandings show evidence of fishery interactions, with bottlenose and striped dolphins most commonly affected, according to analysis across four decades of data and more than 5

In the wild, chimpanzees likely ingest the equivalent of several alcoholic drinks every day

Warming of 2°C intensifies Arctic carbon sink but weakens Alpine sink, study finds

Bronze and Iron Age cultures in the Middle East were committed to wine production

Indian adolescents are mostly starting their periods at an earlier age than 25 years ago

Temporary medical centers in Gaza known as "Medical Points" (MPs) treat an average of 117 people daily with only about 7 staff per MP

Rates of alcohol-induced deaths among the general population nearly doubled from 1999 to 2024

PLOS One study: In adolescent lab animals exposed to cocaine, High-Intensity Interval Training boosts aversion to the drug

Scientists identify four ways our bodies respond to COVID-19 vaccines

Stronger together: A new fusion protein boosts cancer immunotherapy

Hidden brain waves as triggers for post-seizure wandering

[Press-News.org] New mechanism uncovered in early stages of Alzheimer's disease
APP-CTFs disrupt organellar communication, interfering with cellular homeostasis