Novel drug could ‘revolutionise’ Alzheimer’s treatment

The drug troriluzole can reverse memory loss and cognitive decline in mice, and could potentially help to tackle Alzheimer’s disease, new research suggests.

The study from researchers at Auburn University is the first to show how troriluzole can target early-stage alterations associated with Alzheimer’s, providing new hope for potential treatments.

Dr Miranda Reed, a Professor in the department of Drug Discovery at Auburn University and Delivery and the study’s lead researcher, said “By examining how drug treatments can intervene early in the disease process, we aim to develop therapies that might prevent or even cure Alzheimer’s.”

Dr Michael Gramlich, an Assistant Professor of Biophysics, added:

Alzheimer’s disease affects millions of people worldwide, causing progressive memory loss, confusion, and eventually the inability to perform basic tasks.

Alzheimer’s is caused by the accumulation of amyloid plaques and tau tangles in the brain, which disrupt neural communication.

In the early stages, excessive levels of the neurotransmitter glutamate cause damaging overactivity in synapses, the connections between nerve cells.

The new study investigated how troriluzol can maintain normal brain function in mice genetically modified to replicate early Alzheimer’s stages.

Mice treated with troriluzole showed a significant reduction in synaptic glutamate levels and decreased brain hyperactivity.

The results showed that troriluzole not only reduced harmful glutamate levels but also improved memory and learning in the mice, suggesting a maintenance of healthy brain function.

The molecular changes led to tangible improvements: the treated mice performed better in memory tests, such as navigating mazes, indicating that their cognitive functions were restored.

The researchers said: “Our research demonstrates that by targeting synaptic activity early, we may be able to prevent or slow the progression of Alzheimer’s.

“This could revolutionise the way we approach treatment for this disease.”

Understanding why men with prostate cancer are at higher risk of Alzheimer’s

Researchers are searching for a better way to understand why many men with prostate cancer end up with Alzheimer’s disease, and whether it’s the standard hormone therapy treatment or an overactive immune response that actually contributes to the problem.

The hormone therapy, androgen deprivation therapy, known as ADT, treats the cancer by reducing testosterone, which the cancer needs to grow. But androgen is a key regulator of amyloid metabolism and when it’s removed from the equation, more amyloid is left to form the plaques that are a hallmark of Alzheimer’s.

“We know that prostate cancer itself also largely affects men over age 65, which is a population that’s already at a higher risk of Alzheimer’s, simply due to their age,” said Qin Wang, MD/PhD, Georgia Research Alliance Eminent Scholar in Neurodegeneration and inaugural director of the Program for Alzheimer’s Therapeutic Discovery at MCG.

“What is not largely understood is the role ADT may play in the context of cancer and Alzheimer’s disease.”

Wang and her research team at the Medical College of Georgia at Augusta University suspected that the body’s over-active immune response and subsequent inflammation may be at play.

To better understand, they created an animal model with Alzheimer’s disease and cancer, then delivered the ADT for eight weeks, while monitoring androgen levels and tumor size.

“We wanted to first validate our model and also check and see if there were cognitive deficits in that group,” Wang said.

They also developed other animal models. A so-called wild type (without Alzheimer’s or cancer), a group with just Alzheimer’s, and a group with just cancer that received ADT therapy – helped the team further delineate this complex interplay.

The researchers also regularly monitored changes in the blood looking for immune markers.

At the end of eight weeks, they also looked for increased amyloid in the brain, but “to our surprise we didn’t actually see a significant difference in the plaque load in any of the groups.”

They did, however, note a high amount of reactivity in glial cells of the groups with just cancer and the groups treated with ADT.

Glial cells are a part of the central nervous system and typically support nerve cells, helping them function properly. Their hyperactivity is a key indicator of inflammation in the brain, Wang said.

They also noted an increase in pro-inflammatory cytokines, small proteins that trigger an increase in inflammation throughout the body, and a decrease in anti-inflammatory cytokines, particularly in the animals with Alzheimer’s and cancer that received ADT.

The team also looked at the animals’ blood-brain barrier and noted that the same group had significant damage. Under normal circumstances, that barrier protects the brain from harmful substances while allowing essential molecules to pass through.

“That would explain why there is so much more inflammation in that group,” Wang and the team reported.

“The ADT treatment is actually making the blood-brain barrier more permeable. Then these immune cells, which are circulating in higher amounts because of the cancer and the subsequent treatment, can go into the brain – we call it immune cell infiltration – and cause inflammation, which is associated with cognitive decline.”

To intervene and stop the immune cell infiltration, Wang and her team turned to a drug that is already on the market to treat multiple sclerosis and Chron’s disease.

Natalizumab is a disease modifying therapy that works by attaching to immune cells and preventing them from moving across the blood-brain barrier and entering the central nervous system.

Treating the mice who had cancer and Alzheimer’s and cancer with a combination of ADT and natalizumab not only reduced the infiltration but subsequently improved the integrity of the blood-brain barrier.

“Then we looked at inflammation markers and those levels were reduced as well,” Wang said.

“We essentially reduced the pro-inflammatory cycle and improved cognitive function. We now know that it’s not just about the amyloid plaques. The immune system’s response is the contributing factor here.”

Since the drug is already on the market, next steps could include a clinical trial in patients who are undergoing ADT for prostate cancer.

The study has been published the journal Science Advances.

Increased risk of dementia after acute kidney injury

A new study has revealed that acute kidney injury is associated with an increased risk of developing dementia.

Acute kidney injury (AKI), a sudden deterioration in kidney function, is relatively common in older people and is associated with increased morbidity and mortality. Previous studies have suggested a potential link between AKI and brain injury.

The current study, published in the journal Neurology by researchers at Karolinska Institutet and others, examined the association between AKI and different types of dementia.

The researchers analysed data from more than 300,000 individuals over 65 years of age from the Stockholm CREAtinine Measurement (SCREAM) project in Sweden. About one out of four participants experienced at least one AKI episode during an average follow-up of 12 years, and 16% were diagnosed with dementia.

Those who suffered acute kidney injury had a 49% higher risk of developing any form of dementia. When each type of dementia was analysed separately, the risk increase was 88% for Lewy body dementia or dementia caused by Parkinson’s disease, 47% for vascular dementia and 31% for Alzheimer’s disease. The risk increase was higher in people with severe kidney damage requiring hospitalisation or inpatient care.

“Our findings suggest that AKI is not just an isolated event affecting kidney function but may have broader implications, particularly for brain health,” says Hong Xu, assistant professor at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and first author of the paper.

“Identifying acute kidney injury as a risk factor for dementia can lead to earlier intervention, preventive treatment and better patient care,” adds Juan Jesus Carrero, professor at the Department of Medical Epidemiology and Biostatistics Karolinska Institutet and last author of the paper.

The next phase of the research aims to explore the biological mechanisms linking AKI to dementia. The researchers will also evaluate whether different medicines, lifestyle changes and monitoring procedures after acute kidney injury can reduce the risk of developing dementia.

The study was financed by StratNeuro, CIMED, KI foundations, and the Swedish Research Council. The corresponding author Yang Xu, researcher at Peking University Health Science Center and Karolinska Institutet, received funding from the Young Scientists Fund and the National Natural Science Foundation of China.