Human Biomarkers and Pathological Studies
Due to the large gap in the pathological process of neurodegeneration between human and animal models, Dr. Bu's Neurobiology of Alzheimer's Disease Lab at Mayo Clinic recognizes the importance of addressing human relevance in Alzheimer's disease (AD) research.
Team-based science and collaboration
In collaboration with Dennis W. Dickson, M.D., and Ronald C. Petersen, M.D., Ph.D., Dr. Bu's lab analyzed a series of Alzheimer's disease (AD)-related molecules in different regions of the human brain and correlated the data to AD pathology. The key findings from these studies provide new insights into the mechanisms underlying AD, aiding mechanism-based drug design. This work demonstrates the power of collaboration and team-based science, which is a great advantage of Dr. Bu's lab and broadly within the team of scientists at Mayo Clinic.
Role of amyloid-beta accumulation and apoE
By studying regional distribution of amyloid-beta (Aβ), apolipoprotein E (apoE), synaptic markers and other Aβ-related molecules with brains of individuals without dementia, Dr. Bu's lab found that the level of Aβ is correlated positively with synaptic markers but negatively with apoE. This result supports a function of synaptic activity in promoting Aβ accumulation and an important role of apoE in preventing this process. This regional correlation is specific to sporadic but not familial AD as revealed by another study from the lab using brain samples from individuals with normal aging, pathological aging, familial AD and sporadic AD. Rather, in familial AD, the regional distribution of Aβ correlates more closely with the level of amyloid precursor protein (APP) and its processing products.
In addition to the parenchyma, Aβ can also be deposited in the walls of blood vessels as cerebral amyloid angiopathy (CAA). CAA can be seen in up to 90% of brains affected by AD. In a study attempting to understand how sex and APOE4 can affect the risk of CAA, the lab's research team analyzed the CAA pathology in 428 pathologically confirmed brains affected by AD and specifically compared the levels of Aβ and apoE in brains with severe CAA versus those without CAA. It was found that males have higher overall CAA scores compared with females, and APOE4 carriers have a higher chance of having more-severe CAA pathology.
Dr. Bu's lab also contributes to the field of human clinical studies. By collaborating with biostatisticians, the lab studied the impact of apoE2 on cognitive functions with The National Alzheimer's Coordinating Center (NACC) dataset. Compared with APOE4, APOE2 displayed a protective effect against cognitive decline across the life span. Moreover, this effect may be independent of amyloid accumulation.
The Neurobiology of Alzheimer's Disease Lab is committed to solving the problem of Alzheimer's disease by studying apoE and TREM2 biology and pathobiology using the data from human and animal models to complement one another. Ongoing efforts in human study are dedicated to integrating different levels of data, such as human clinical data, neurological data, RNA sequencing data and animal behavior data, to gain a more comprehensive understanding of AD etiology, pathology and treatment.
Shinohara M, Kanekiyo T, Tachibana M, Kurti A, Shinohara M, Fu Y, Zhao J, Xianlin H, Sullivan PM, Rebeck GW, Fryer JD, Heckman MG, Bu G. APOE2 is associated with longevity independent of Alzheimer's disease. eLife. 2020; doi:10.7554/eLife.62199
Liu CC, Yamazaki Y, Heckman MG, Martens YA, Jia L, Yamazaki A, Diehl NN, Zhao J, Zhao N, DeTure M, Davis MD, Felton LM, Qiao W, Li Y, Li H, Fu Y, Wang N, Wren M, Aikawa T, Holm ML, Oue H, Linares C, Allen M, Carrasquillo MM, Murray ME, Peterson RC, Ertekin-Taner N, Dickson DW, Kanekiyo T, Bu G. Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease. Alzheimer's & Dementia. 2020; doi:10.1002/alz.12104