ADVERTISEMENT

Molecular Gender Differences In Alzheimer’s Disease May Point To A New Drug Target

Alzheimer’s disease is the most common neurodegenerative disorder with an estimated 44 million affected people worldwide. The typical symptoms range from memory loss, confusion, short attention span to a wide variety of changes in mood and behavior, with devastating and life-changing effects for both patients and their families.

While it is widely recognized that Alzheimer’s susceptibility is higher among elderly persons and individuals with a family history of the disease, a less well known risk-associated factor is gender. At an age of 65, on average 1 in 6 females will develop the disease during the remainder of their life, whereas only 1 in 11 males are expected to become affected. This difference remains significant even when adjusting the comparison between the genders for a longer average life expectancy of women. Moreover, differences between the sexes also influence the clinical features of Alzheimer’s disease: A significantly more severe pathology and faster brain atrophy rate has been observed in women than in men.

ADVERTISEMENT

The molecular causes of these gender disparities and the mechanisms by which they modulate the disease are still unknown, but their understanding may pave the way to the discovery of new drug targets and more effective gender-tailored treatments.

In a recent study, scientists from the Luxembourg Centre for Systems Biomedicine used molecular profiling experiments to study the brain samples of more than 650 deceased Alzheimer patients and control subjects of both sexes. They showed that some of the disease-associated activity alterations at the level of individual biomolecules are indeed gender-specific. In particular, they identified a sex-linked regulatory gene, called ubiquitin-specific peptidase 9 (or USP9), that displays both significant activity changes in Alzheimer’s and a diverse activity profile between the genders.

Molecular surface representation of a sub-structure in the ubiquitin-specific peptidase 9 (USP9 putative UBL domain, crystal structure derived from PDB database entry 5VDB). (Credit: Enrico Glaab)

When studying the USP9 gene in more detail using cell culture and zebrafish experiments to determine the effects of knocking the gene down, the researchers could show that the expression of a known Alzheimer’s disease-associated gene was reduced in both models. This gene encodes the microtubule-associated protein tau (MAPT) and forms so-called “tangle structures“ in Alzheimer’s as a major pathological hallmark of the disease.

NMR solution structure of human tau phosphothreonine peptide (ribbon and wireframe representation, NMR structure derived from PDB database entry 1I8H). (Credit: Enrico Glaab)

To better understand the molecular signaling network that interconnects USP9 and MAPT, the scientists then created a computer model that interlinks the obtained molecular profiling data from relevant genes with known regulatory information from the literature and public databases. They identified an experimentally confirmed signaling chain that explains how USP9 activity can modulate MAPT expression and is consistent with the measured profiling data.

ADVERTISEMENT

Interestingly, the analysis shows that USP9 can influence MAPT activity via multiple tau regulators, including proteins that have previously been suggested as candidate drug targets for Alzheimer’s. Thus, altering USP9 activity pharmacologically to exploit its combined effects on multiple direct MAPT regulators has the potential to exert a stronger effect on MAPT-related pathological alterations as a new intervention strategy against Alzheimer’s disease.

The detailed study findings are discussed in the article Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies in the journal Molecular Neurobiology. The work was led by Enrico Glaab from the Luxembourg Centre for Systems Biomedicine at the University of Luxembourg.

Comments

READ THIS NEXT

How Does The Latitudinal Dependency Of The Cloud Structure Change Venus’ Atmosphere’s Temperature And Circulation?

Clouds are not located at the same altitude everywhere in Venus’ atmosphere. They are 10km lower at the poles than […]

Use Of DNA Analysis In Identifying The DPS And Population Origin Of Highly Migratory Atlantic Sturgeon

There are between 25 and 27 species of sturgeons in the temperate waters of the Northern hemisphere, and populations in […]

Water Reuse And The Circular Economy

Water is essential for human survival and well-being and plays an important role in many sectors of the economy. However, […]

What Is The Richest Country In Africa?

What is the richest country in Africa? Is it Egypt? Nigeria? Maybe Morroco? Containing over one-seventh of the world’s population […]

What Is A Sow Bug?

What is a sow bug? A sow bug, also sometimes known as a woodlouse, is an oval creature not larger […]

First Image Of A Newborn Planet Captured

In the many years that astronomers have been watching the skies, they’ve hoped to get a glimpse of the moment […]

A Universal Deposition For Large-Area New Generation Perovskite Photovoltaics

The game-changing discovery of photovoltaic perovskites has heralded a new generation in photovoltaic technology. Now, their future commercial exploitation might […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?