MicroRNA a Potential Therapeutic Target for Alzheimer’s and Age-Related Macular Degeneration

Louisiana State University Health Sciences Center researchers in New Orleans have shown that TREM2, an innate immune receptor protein essential to the clearing of waste from the brain and retina, is diminished in age-related macular degeneration (AMD), identifying a key molecular pathway and possible therapeutic target.

Loss of function of TREM2 has been associated with several pathogenic events in different progressive neurological diseases such as Alzheimer’s. The research paper, “microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration,” was published in PLOS One.

During the normal physiological processes, the brain and retina produce large quantities of waste products, such as amyloid protein, a hallmark of Alzheimer’s disease. This waste is cleared in a process that includes the TREM2 protein, localized in highly specialized cells called microglia which constitute the main form of active immune defense in the central nervous system (CNS).

When the clearance system is not working properly, these waste products accumulate and lead to the formation of harmful structures, such as amyloid plaques. Mutations and loss of function of TREM2 have been linked to deficiencies in phagocytosis, the innate-immune system, axonal and synaptic abnormalities, and progressive dementia in several progressive neurodegenerative diseases of the CNS such as sporadic amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease.

Researchers studied the behavior of TREM2 in human retinal tissues affected by age-related macular degeneration (AMD), a neurodegenerative disease of the human retina characterized by the progressive loss of central vision. The studies also involved animal models of the disease and microglial cells.

Results showed a lowered and insufficient amount of TREM2 protein associated with the disease — a possible contributor to the deficient waste-clearing abilities and consequent waste accumulation and neurodegenerative inflammation characteristic of these diseases. Moreover, researchers found a likely effector of such downregulation, the microRNA-34a, a pro-inflammatory molecule found to be up-regulated in the tested samples.

“These scientific findings further indicate that getting rid of the excessive miRNA-34a to restore normal TREM2 abundance may provide a highly effective therapeutic strategy for the treatment of both degenerative diseases of the brain, such as Alzheimer’s disease, and progressive diseases of the retina, such as age-related macular degeneration,” lead author Prof. Walter Lukiw said in a press release.