Not to be forgotten: Alzheimer’s disease

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Joël Rollinger

It is estimated that currently 47 million people worldwide are living with dementia. Alzheimer’s disease is the most common neurodegenerative disorder and the major cause of dementia (65%). Every 3 seconds, someone in the world develops dementia. A survey in 2018 estimated that more than 9,000 people suffer from Alzheimer’s disease in Luxembourg. With age being considered the most important risk factor, this number will considerably increase within the next decades due to the increasing life expectancy.

Patients exhibit severe memory impairments, cognitive decline and neuropsychiatric symptoms. While the clinical symptoms are rather well defined, the molecular mechanisms underlying brain dysfunction in Alzheimer’s patients are still poorly characterized. As a consequence, there is currently no treatment available to slow down or cure the disease. At the LCSB, we are studying the underlying mechanisms of neurodegenerative diseases to ultimately develop new ways to treat the disease.

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Deep look into the brain

Alzheimer’s disease is complex and many factors contribute to its development. For many years, the research community focused almost exclusively on abnormal accumulation of the amyloid protein, which was believed to be the cause of neuronal loss in brain of Alzheimer’s patients. Today we know that this represents only one piece of the puzzle. At the LCSB, researchers are trying to unravel the roles of cell types other than neurons in the progression of the disease. Indeed, the glial cells are 10 times more abundant than nerve cells in the brain and insure key functions in health and disease. Astrocytes provides energy and nutrients to neurons but also modulate their activity. Microglia are the brain specific immune cells, which under normal conditions defend it against pathogens.

In order to understand how glia cells contribute to the initiation and progression of the disease, we need to look deep into the diseased brain. We are particularly interested in the hippocampus – the part of the brain responsible for new memory formation and that is one of the most vulnerable brain regions in Alzheimer’s disease. To this end, we analyse human brain sampes of Alzheimer’s patients that have decided to donate their brains after their death, until now provided from the Montreal Brain Bank, Canada. This a very precious gift to research and we are proud that a brain bank is currently being established in Luxembourg.

We use super-resolution microscopy to observe these tissues and study how the shape and function of the glia cells changes during the course of the disease, how they differ from healthy brains or from samples with other types of dementia. These techniques allow us to magnify the tiniest structures within the cells at nanoscale. On the computer, we use artificial intelligence approaches to analyse and compare ten thousands of cells at the same time to get a clear picture of their role and fate in Alzheimer’s disease. We found that some groups of microglia and astrocytes are becoming toxic and could exacerbate the death of neurons.

More women than men affected

Strikingly in Alzheimer’s disease, elderly women are afflicted much more frequently than men, with about 2/3 of the patients being female. This gender difference, which cannot be explained by the longer average lifespan of women alone, is studied by LCSB scientist Dr. Enrico Glaab. For his discovery of the role of the gene USP9 in Alzheimer’s, he won the Global NeuroDiscovery Challenge by the Geoffrey Beene foundation  in a neck to neck competition with Harvard in 2013. He showed that USP9 has different properties in men and women with AD. Doing experiments in zebrafish and cell culture models, he and his collaborators have shown a functional role of this gene in the regulation of the Alzheimer-associated protein tau, the protein that accumulates in the characteristic neurofibrillary tangles in the brains of Alzheimer’s patients.

Glaab and his colleagues deciphered the molecular process through which USP9 may contribute to the molecular gender differences observed  in Alzheimer’s and provided a new candidate target for therapeutics. In addition, they also discovered a gene variant in the gene ADAM 17 that is associated with late-onset familiar Alzheimer’s disease.

Preventing dementia

Treatment and prevention go hand-in-hand. The LCSB is also in charge of the national Programme for Dementia Prevention (pdp) funded by the Ministry of Health. This program aims to delay the onset of dementia in people with early signs of mild cognitive impairment. This can be done by working on risk factors like obesity, high blood pressure, depression, hearing loss, poorly controlled diabetes, and even smoking, as well as social isolation and lack of exercise.

People who are suspected of mild cognitive impairment and who present elevated risk factors can be referred by their doctor to the Programme for Dementia Prevention. There, they will be carefully assessed through specific memory, attention and speech tests accompanied by lifestyle questionnaires. The results are then analysed to suggest concrete measures: dietary recommendations, courses and social activities such as sports classes, or memory training for which the participant receives vouchers. Thus, pdp offers many opportunities of getting the risk factors for dementia under control. Every case of dementia we can prevent with pdp is a wonderful success!

LCSB’s Alzheimer’s research has been supported by Rotary’s Espoire en Tete, private donation, Fondation Gustave et Simone Prévot, Geoffrey Beene Foundation, and Luxembourg’s Ministry of Health