Block a “Death Complex” brain slows down the Alzheimer’s

Summary: scientists have discovered that a toxic complex formed between NMDA receptors and TRPM4 channels promotes the death of neurons in Alzheimer’s disease. Using a new molecule called FP802, researchers could separate this “death complex” in mice, avoiding cognitive deterioration, synapse loss and mitochondrial damage.

The treatment also reduced the accumulation of amyloids, which suggests that it could offer broader protection than existing therapies. While they are still in the early stages, the findings open a new promising route to treat Alzheimer’s and other neurodegenerative diseases such as ELA.

Key facts

Identified toxic complex: The NMDAR/TRPM4 complex causes neuronal death and feeds Alzheimer’s progression. Fragment candidate: FP802 interrupted the complex in mice, preserving memory, synapses and mitochondrial health. Novel approach: It is aimed at the mechanisms of cell death of the summary instead of directly removing the amyloid banks.

Source: Heidelberg University

A molecular mechanism that contributes significantly to the progression of Alzheimer’s disease has been discovered by a research team led by neurobiologist Prof. Dr. Hilmar Bading of Heidelberg University.

In joint experiments with researchers from the University of Shandong (China), the equipment, using a Alzheimer’s mouse model, showed that a neurotoxic protein protein complex is responsible for nerve cells in the brain dead and the resulting cognitive decrease.

According to scientists, this finding opens new perspectives for the development of effective treatments.

The protein-protein complex, known from previous studies, consists of the NMDA receiver and the TRPM4 ion channel. The NMDA receptors, who participate in the transmission of the signal between the nerve cells, are found on the surface of the cells and are present both in the synapses and outside these points of contact between the nerve cells.

They are activated by a biochemical messenger, the neurotransmitter glutamate. While the activation of synaptic NMDA receptors in the brain is critical for the survival of nerve cells, as well as the preservation of cognitive skills, TRPM4 provides the toxic properties of NMDA extra -amazing receptors.

Together they build a “complex of death” that can cause damage, as well as the death of nerve cells, explains Hilmar Bading, who runs the Institute of Neurobiology at the Interdisciplinary Center for Neurociplinaries of the University of Heidelberg (IZN).

The NMDAR/TRPM4 neurotoxic complex is present at much higher levels in Alzheimer’s mice than in healthy animals, according to research.

Using the new FP802 pharmaceutical compound, a so -called “twin interface inhibitor” discovered in previous studies of Prof. Bading and his team in the IZN, the international research team showed that the NMDAR/TRPM4 complex plays a key role in the progression of the cognitive decline.

In experiments in a mouse model, they managed to break the mortal protein protein complex with this neuroprotective molecule. FP802 joins the so -called “Twinf” contact surface through which TRPM4 interacts with NMDA receptors, thus blocking physical interaction between the two proteins and dissolving the complex.

“In Alzheimer’s mice treated with the molecule, the progression of the disease slowed down significantly,” says Dr. Jing Yan, a Prof. Bading team researcher who now works fundamentally Pharma, a biotechnological branch of the IZN Neurobiology Institute.

Typical cellular changes due to Alzheimer’s disease, including the loss of synapses and structural and functional damage to mitochondria, cell powers, developed only in a limited degree or not, the scientists report.

Cognitive skills such as learning and memory remained largely preserved. In addition, the characteristic formation of beta-amyloid deposits in the brain was significantly reduced.

According to Prof. Bading, this approach differs primarily from previous treatment strategies for Alzheimer’s disease.

“Instead of addressing the formation or elimination of amyloid of the brain, we are blocking a cellular downstream mechanism, the NMDAR/TRPM4 complex, which can cause the death of nerve cells and, in a feedback circuit that promotes the disease, promotes the formation of amyloid deposits,” says Heidelberg’s neurobiologist.

In previous studies, the equipment was able to demonstrate comparable neuroprotective effects of the TWINF FP802 interface in disease models for amyotrophic lateral sclerosis (ALS), in which the NMDAR/TRPM4 complex also plays a role.

Therefore, researchers believe that they have found in the novel inhibitor a potentially applicable pharmacological principle that could delay or even stop the progression of neurodegenerative diseases such as Alzheimer’s and ELA. Prof. Bading informs, however, that a prospective clinical application remains far.

“The above results are quite promising in the preclinical context, but integral pharmacological development, toxicological experiments and clinical studies are necessary to make a possible application in humans,” emphasizes the scientist.

In close cooperation with the fundamental pharmacy, the neuroprotective molecule FP802 will be optimized for this in the coming years.

Financing: The investigation was funded by the German Research Foundation, the European Research Council, the former Federal Ministry of Education and Research, the National Foundation of Natural Sciences of China and the province of Shandong of Eastern China.

The results were published in the Molecular Magazine Psychiatry.

About this genetics and the research news of Alzheimer’s disease

Author: UTE Mueller-Dert
Source: Heidelberg University
Contact: UTE Mueller-Dert-University of Heidelberg
Image: The image is accredited to Neuroscience News

Original research: open access.
“The NMDAR/TRPM4 death complex is an important promoter of the progression of the disease in the 5xfad mouse model of Alzheimer’s disease” by Hilmar Bading et al. Molecular psychiatry

Abstract

The NMDAR/TRPM4 death complex is an important promoter of the progression of the disease in the 5xfad mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder, characterized by cognitive deterioration and neuronal degeneration.

The formation of β amyloid and neurofibrillary tangles are key morphological characteristics of AD pathology. However, the specific molecules responsible for cell destruction triggered by the proteinopathies of β and tau amyloid have not yet been identified.

Here we use AD 5xfad model of AD to investigate the role of a recently discovered death signaling complex consisting of the N-Methyl-D-Spartate (NMDAR) extra

The NMDAR/TRPM4 death complex is responsible for toxic glutamate signaling, which has been involved in AD pathogenesis.

We detect an increase in the formation of the NMDAR/TRPM4 death complex in 5xfad mice brains. This increase was blocked by the Oral application of FP802, a small molecule TWINF interface that can interrupt and, therefore, detoxify the NMDAR/TRPM4 death complex.

FP802 treatment avoided the cognitive decrease in 5xfad mice evaluated using a series of memory tasks. He also retained the structural complexity of the dendrites, avoided the loss of synapses, reduced the formation of the β -amyloid plate and protected against pathological alterations of the mitochondria.

These results identify the NMDAR/TRPM4 death complex as an important promoter of the progression of AD disease, amplifying potentially perpetual pathological processes initiated by β amyloid.

Twinf interface inhibitors offer a new therapeutic pathway, which serves as an alternative or complementary treatment to cleaning β -brain β antibodies of ad.