Work in the Neurobiology of Alzheimer's Disease Lab includes collaborations with neurologists and neuropathologists at Mayo Clinic. In collaboration with Dennis Dickson, M.D., and Ronald C. Petersen, M.D., Ph.D., Dr. Bu's lab analyzed brain regional distributions of various Alzheimer's disease (AD)-related molecules in human brain samples. The key findings from these studies have strong implications in deciphering disease mechanisms and in the design of mechanism-based therapies. Such work also exemplifies the power of collaboration and team-based science.
Using brain samples from non-demented individuals, Dr. Bu's lab has shown that while the regional distribution of synaptic markers positively correlates with those of soluble amyloid beta (abeta), the regional distribution of apoE negatively correlates with the distribution of insoluble abeta. These results support a function of synaptic processes in promoting abeta accumulation and an important role of apoE in preventing abeta accumulation. In another study using brain samples from individuals with normal aging, pathological aging, familial AD and sporadic AD, the lab discovered distinct pathological features between familial and sporadic AD. Specifically, while the regional distributions of synaptic markers correlate strongly with those of abeta in sporadic AD, such correlation is much weaker in familial AD. Rather, in familial AD, the regional distribution of abeta more closely correlated with those of amyloid precursor protein (APP) and its processing products.
Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, Dr. Bu's lab recently examined the effects of APOE4, sex and pathological components on cerebral amyloid angiopathy (CAA) in people diagnosed with AD. Autopsied brain samples from 428 pathologically confirmed people with AD were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of abeta and APOE by ELISA in the temporal cortex.
After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, Dr. Bu's group found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent soluble and insoluble abeta 40, and insoluble apoE, were significantly elevated in individuals with severe CAA or APOE4. The ratio of abeta 40/42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble abeta 40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble abeta 42, the levels of apoE correlated regardless of CAA status. These results indicate that sex and APOE genotype differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of abeta 40 and apoE.