dementia Archives - Sanford Burnham Prebys

Tag: dementia

Institute News

Mutations in protein receptor gene linked to Alzheimer’s disease

AuthorGreg Calhoun
Date

January 7, 2025

Elena Pasquale profile photo
Elena Pasquale, PhD, is a professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys.

New research on four variants in the EPHA1 gene reveals how its genetic typos may contribute to risk of dementia

Upon inspecting the DNA sequences in patients suffering from Alzheimer’s disease, scientists have found evidence of an inconspicuous conspirator.

The EPHA1 gene contains the blueprint for the EPHA1 receptor protein, one of 14 such receptor proteins in the Eph receptor family. Relatively little is known about EPHA1 when compared to many of its siblings, making it difficult for researchers to ascertain why changes in its source code would contribute to such a debilitating disease.

Scientists at Sanford Burnham Prebys published results on December 18, 2024, in the Journal of Biological Chemistry, detailing the effects of four miniature mutations of just a single typo each in the sequence of nucleotides forming the EPHA1 gene.

These seemingly minor mutations are known as single nucleotide polymorphisms (SNPs), and they can lead to larger issues depending on where the typos fall in the sequence of a gene. The Sanford Burnham Prebys team focused on four missense mutations that are caused when SNPs result in different amino acids being used to build the EPHA1 receptor protein.

“Our data show that all four Alzheimer’s mutations we have characterized disrupt EPHA1 physiological signaling, and that the specific effects depend on the particular mutation,” said Elena Pasquale, PhD, professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys.

The team reported that the functional consequences of EPHA1 missense mutations identified in patients suffering from Alzheimer’s disease included misplacement of EPHA1 within cells, decreased protein stability and dysregulated signaling.

“To continue advancing knowledge on this topic, more work is needed to uncover the physiological role of the different EPHA1 signaling features and how their disruption may lead to neurodegeneration,” said Pasquale.

Additional authors on the study from Sanford Burnham Prebys include Mike Matsumoto and Sara Lombardi, PhD. Maricel Gomez-Soler, PhD, now works at Crinetics Pharmaceuticals in San Diego. Bernhard C. Lechtenberg, PhD, now works at the Walter and Eliza Hall Institute of Medical Research in Parkville, Australia.

Institute News

New potential way to slow advance of Alzheimer’s

AuthorJessica Moore
Date

July 27, 2016

Silver-stained brain tissue showing senile plaque

Like weeds taking over a garden, the brains of Alzheimer’s patients become congested with clumps of protein. These clumps arise when a peptide called amyloid beta takes a shape that sticks to other amyloid beta molecules and converts them to the same sticky form, causing a chain reaction. The sticky form of amyloid beta is toxic, so as amyloid plaques accumulate, neuronal connections, and eventually whole neurons, are lost.

Research from the laboratory of Huaxi Xu, PhD, professor in the Degenerative Diseases Program, suggests a new possible way to minimize the generation of amyloid beta and slow the advance of this tragic disease. Alzheimer’s, which affects more than 5 million people and is the 6th leading cause of death in the US, destroys patients’ memory and, at later stages, their ability to communicate and understand their surroundings.

“Our results could eventually help us discover therapeutics that address the progression of Alzheimer’s disease,” said Xu. “That would be a big step forward—no such treatment has yet been approved.”

In the new study, published in the Journal of Neuroscience, Timothy Huang, PhD, a postdoc in Xu’s lab, examined the function of a receptor called SORLA because variants of the gene encoding it had been linked to early-onset Alzheimer’s. SORLA had also been shown to affect trafficking—transport from one cellular compartment to another—of amyloid beta’s precursor. Amyloid beta is generated only in acidic compartments, where the precursor is cut to yield the toxic form, so trafficking has a big impact on how much amyloid beta is made.

“We found that SORLA, with its partner SNX27, moves the amyloid precursor protein away from the acidic compartment, where it would be cut into amyloid beta, to the cell surface,” said Huang. “There, the amyloid precursor protein is cut in a way where it cannot be cut into amyloid beta.”

“Modulating trafficking of the amyloid precursor protein through SORLA could be a new way to treat Alzheimer’s,” added Xu. “Other strategies of decreasing levels of amyloid beta, such as inhibiting the enzyme that cuts the precursor, have failed in the clinic, so new approaches are needed.”

Xu and Huang next plan to investigate whether enhancing amyloid precursor trafficking via SORLA reduces loss of neurons and improves cognitive function in an animal model of Alzheimer’s.

The paper is available online here.