Chemical Compound Can Restore Neural Function in Familial Alzheimer’s, Study Finds

 

A mutation in a gene linked to familial Alzheimer’s disease promotes the disease by reducing the points of contact between nerve cells and impairing neuronal communication, a study has found.

A chemical compound, called EVP4593, partially rescued the mutation’s negative effects, suggesting it may hold a potential therapeutic role for familial Alzheimer’s.

The study, “Antagonist of neuronal store-operated calcium entry exerts beneficial effects in neurons expressing PSEN1ΔE9 mutant linked to familial Alzheimer disease” was published in the journal Neuroscience.

Mutations in the amyloid precursor protein (APP) and presenilin (PS1 and PS2) genes cause an inherited form of Alzheimer’s disease, or familial Alzheimer’s. Most familial Alzheimer’s cases are caused by mutations in the PS1 gene, which codes for a protein called presenilin.

This protein belongs to a complex of molecules that splits amyloid precursor protein to produce beta amyloid, whose toxic aggregates are thought to be at the center of the toxic protein clumps and neuroinflammation that drive Alzheimer’s.

Now, a team of researchers at Russia’s Peter the Great St. Petersburg Polytechnic University (SPbPU) investigated a mutation in the PS1 gene, called PSEN1ΔE9, found in a group of familial Alzheimer’s patients in Finland. The researchers investigated how the mutation, which removes a part of the PS1 gene, affected disease progression.

They began by introducing the mutation, tagged with a fluorescent protein, in neurons present in the hippocampus, a brain region linked to memory and spatial navigation. They then looked at how the mutation affected the formation of dendritic spines, small protrusions that emerge from the dendrites (branched extensions) of neurons and where the majority of synapses occur. Synapses are the junctions between two nerve cells that allow them to communicate; dendritic spines typically have a mushroom-like shape.

Compared to controls (healthy) neurons, cells with the PSEN1ΔE9 mutation had significantly fewer mushroom spines and more thin spines, meaning that the area of contact between neurons was reduced.

“Loss of mushroom synaptic spines may be related to initiation and progression of cognitive decline in [Alzheimer’s disease],” the researchers stated.

The mutated neurons showed increased activity of calcium “gates” called store-operated calcium channels. Calcium is required for the correct release of neurotransmitters, chemical substances produced in response to nerve signals that act as messengers and allow correct communication between nerve cells.

Blocking the activity of these calcium gates with a chemical compound — called EVP4593 — partially rescued mushroom spine loss in mutated neurons and restored neural functions close to normal levels.

Overall, these results suggest that chemicals like “EVP4593 may have potential as therapeutic agents for treating [familial Alzheimer’s disease] patients with PSEN1ΔE9 mutation,” the researchers said.

However, the team noted that because Alzheimer’s is a multifactorial disease, other pathways also contribute to disease onset and progression, and as such “selection of potential [Alzheimer’s disease] therapeutic agents may require careful analysis of underlying causes of the disease for each individual patient.”