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UCI Generates Preliminary Evidence of a Gene Mutation That May Reduce Risk of Alzheimer’s Disease

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Through new developments in Alzheimer’s research, UCI scientists have uncovered evidence of P522R, a particular gene mutation that may aid in minimizing the risk of developing Alzheimer’s disease. 

Alzheimer’s disease is a progressive disorder that slowly deteriorates memory and thinking skills in the brain, eventually leading to a loss in the ability to complete simple tasks such as  facilitating a conversation or responding to a stimulus in the environment.

With the discovery of the disease in 1906 by Dr. Alois Alzheimer, its causes today are focused on two suspects: plaques and tangles in proteins.

Beta-amyloid, fragments of a large protein that is located in the bilipid membrane of nerve cell walls, can form plaques when the fragments cluster together due to their chemically “sticky” nature. Although these amyloid plaques are destructive, the most damaging clumps have been linked to smaller groups of clustered fragments. These smaller clumps block cell-to-cell communication at synapses and also signal immune system cells that trigger inflammation and consume disabled cells nearby.

Tau, a protein vital to a neuron’s internal support and transport system, helps carry nutrients and other chemicals by keeping strands straight in a cell in order to facilitate feasible movement. In patients with Alzheimer’s, tau changes shape and instead collapses into twisted proteins referred to as tangles. The strands in the cells no longer remain rigid and the tangles formed do not allow for nutrients and other important substances to reach target cells. As a result, those target cells will deteriorate.

At the scale of the human brain, the effects of Alzheimer’s disease are especially prevalent. With the accumulation of amyloid plaques and tau tangles, the hippocampus and entorhinal cortex, parts of the brain essential to memory formation, are areas in the organ where damage initially appears. As a result, individuals with early-stage Alzheimer’s disease start to experience memory loss. Through the continuous death of neurons within these regions, the brain’s tissue begins to shrink as well.

The CDC reported that “as many as 5.8 million Americans” had Alzheimer’s disease in 2020. Since individuals of age 65 and older can develop Alzheimer’s, increasing age is considered the most important risk factor. However, reducing the risk of Alzheimer’s disease has recently become a possibility through particular findings that emerged in a study directed by faculty at UCI.

Conducted in the laboratory of Professor of Neurobiology and Behavior Mathew Blurton-Jones, the study led by assistant project scientist Christel Clae was centered around a mutation known as P522R, a variant of the PLCG2 gene.

The PLCG2 gene provides functional instructions for an enzyme called phospholipase C gamma 2 (PLCγ2), which has the ability to call upon reinforcements that can attack any recognized foreign invaders like bacteria and viruses, playing an important role in immune response within the nervous system. Regarding such reinforcements, brain immune cells such as microglia have become key factors in studies of Alzheimer’s disease. 

Responsible for supporting the central nervous system, microglia initiate neuroprotection with the release of growth factors and anti-inflammatory cytokines. They also promote phagocytic clearance in order to maintain homeostasis within the brain. Since they have the ability to clear phagocytes, beta-amyloid fragments can be degraded with the release of degrading enzymes. Due to this function, microglia are being increasingly considered as potential therapeutic treatments for improving Alzheimer’s disease.  

In their published paper with the Alzheimer’s Association, the UCI scientists described their use of CRISPR/Cas9 technology to create two strains of genes: a wild-type PLCG2 sample and a mutated P522R sample from human pluripotent stem cells. These developed strains were then transplanted into chimeric Alzheimer’s disease and wild-type mice.

Their experimental results had shown that the P522R mutation had successfully increased expression levels of microglial genes. This expression also demonstrated its ability to later trigger the induction of additional white blood immune system cells (T-cells) and other antigen processes to the brain. 

With the decreased efficiency of microglia and T-cells observed as individuals age, the results of this study can offer a positive outlook towards potential future treatments that can be used to reduce the risk of Alzheimer’s disease.

Further research can still be developed on both subjects, in order to fully show how both of these neural and immune components slow the progression of the brain disorder. 

Korintia Espinoza is a STEM staff writer for the winter 2022 quarter. She can be reached at