Alzheimer's disease is a slow progression over time and lost cognitive function, but it does kill people in the end. How exactly does the pathology of Alzheimer's disease cause the widespread death of neurons that is characteristic of the late stages of the condition and the eventual cause of death? There are many ways of building an answer to this question, as one can focus on many different parts of the chain of cause and consequence that must exist in the less well studied spaces that exist between the more well studied aspects of Alzheimer's biochemistry. On the one hand protein aggregation of amyloid-β and tau, and on the other hand disrupted metabolism and cell death in neurons, and in between a great deal of dark matter.
In today's open access paper, researchers focus on a mechanism that is closer to neuronal cell death in the chain of cause and effect than is the case for protein aggregation. Two receptors on the cell surface of neurons combine in the context of other Alzheimer's disease cellular dysfunction to cause cell death via a range of severe downstream consequences. The researchers found a way to specifically interfere in the interaction between these two receptors, a necessary approach to therapy, as both are individually essential to cell function and thus cannot be depleted. This interference appears to slow the pathology of Alzheimer's disease in a mouse model of the condition. Interestingly, it has also shown promise in other neurodegenerative conditions, such as in models of ALS.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by cognitive decline and neuronal degeneration. The formation of amyloid β plaques and neurofibrillary tangles are key morphological features of AD pathology. However, the specific molecules responsible for the cell destruction triggered by amyloid β and tau proteinopathies in AD has not yet been identified.
Here we use the 5xFAD mouse model of AD to investigate the role of a recently discovered death signaling complex which consists of the extrasynaptic N-methyl-D-aspartate receptor (NMDAR) and the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 death complex is responsible for toxic signaling of glutamate, which has been implicated in AD pathogenesis. We detected an increase in NMDAR/TRPM4 death complex formation in the brains of 5xFAD mice. This increase was blocked by the oral application of FP802, a small molecule TwinF interface inhibitor that can disrupt and thereby detoxify the NMDAR/TRPM4 death complex.
FP802 treatment prevented the cognitive decline of 5xFAD mice assessed using a series of memory tasks. It also preserved the structural complexity of dendrites, prevented the loss of synapses, reduced amyloid β plaque formation, and protected against pathological alterations of mitochondria. These results identify the NMDAR/TRPM4 death complex as a major promoter of AD disease progression, amplifying potentially self-perpetuating pathological processes initiated by amyloid β. TwinF interface inhibitors offer a novel therapeutic avenue, serving as an alternative or complementary treatment to antibody-mediated clearing of amyloid β from AD brains.
View the full article at FightAging
