UCI researchers identified Alzheimer’s disease brain neural circuit alterations

Researchers for years have struggled to develop therapies for treating Alzheimer's disease (AD). Thus far, these therapeutic approaches have been guided primarily by focusing on alleviating neuropathological features along with minimizing the loss of the neurotransmitters including acetylcholine. Now, a new study published in The Journal of Neuroscience by UCI School of Medicine researchers explores how AD affects the brain's wiring, concentrating on a specific brain area called the subiculum, one of the first brain areas impacted by AD. This opens the door to exciting, innovative treatments for AD that focus on the possibility of repairing impaired brain circuitry rather than changing brain chemistry.

Led by Xiangmin Xu, PhD, a UCI Chancellor’s Professor of anatomy and neurobiology and director of the Center for Neural Circuit Mapping (CNCM), the research team utilized an advanced technique known as monosynaptic rabies viral tracing in a mouse model of AD and normal mice to track how brain connections to the subiculum change with age, as well as between males and females. The study revealed that these connections, particularly those from areas involved in learning and memory, changed differently for males and females and with age, suggesting that AD may disrupt the brain's networks in complex ways that contribute to memory and learning problems. These findings are in general agreement with the understudied observation that AD impacts male and female AD patients differently.

“Our study is the first to use a novel viral genetic tool to map neuronal circuit changes of the subiculum in AD,” said Xu. “Because circuit defects in AD occur long before symptoms, AD treatments may be more effective by addressing the disease earlier.”

As the research team looks to the future, armed with the powerful monosynaptic rabies tracing technique and other state-of-the-art viral genetic tools, they are set to delve deeper into AD’s effects on brain circuits in other brain regions. Moreover, they will continue to investigate the key pathways that are disrupted in AD and the functional role of these pathways.

Xu's innovative research was led by first author Qiao Ye (PhD student), with critical contributions from Gocylen Gast, Erik Wilfley, Hanh Huynh, Chelsea Hays of the Xu Lab and Todd Holmes, a professor of physiology and biophysics in UCI School of Medicine.

This work was supported by National Institutes of Health grants RF1AG065675, RF1MH120020, S10MH124715 and R35 GM127102.

Read the full article, “Monosynaptic rabies tracing reveals sex- and age-dependent dorsal subiculum connectivity alterations in an Alzheimer's disease mouse model,” in the April 17 issue of The Journal of Neuroscience.

About the UCI School of Medicine

Each year, the UCI School of Medicine educates more than 400 medical students and nearly 150 PhD and MS students. More than 700 residents and fellows are trained at the UCI Medical Center and affiliated institutions. Multiple MD, PhD and MS degrees are offered. Students are encouraged to pursue an expansive range of interests and options. For medical students, there are numerous concurrent dual degree programs, including an MD/MBA, MD/MPH, or an MD/MS degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Program in Medical Education for Leadership Education to Advance Diversity-African, Black and Caribbean (PRIME LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit medschool.uci.edu.