Frontal Cortex And Striatal Cellular And Molecular Pathobiology In Individuals With Down Syndrome With And Without Dementia
Although, by age 40, individuals with Down syndrome (DS) develop amyloid-Î² (AÎ²) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimerâ€™s disease (AD), not all people with DS develop dementia. Whether AÎ² plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD âˆ’) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as AÎ² and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD âˆ’ cases. Expression profiling of single pS422 labeled FC layer V and VI neurons was also determined using laser capture microdissection and custom-designed microarray analysis. Analysis revealed that cortical and striatal AÎ² plaque burdens were similar in DSD + and DSD âˆ’ cases. In both groups, most FC plaques were neuritic, while striatal plaques were diffuse. By contrast, FC AT8-positive NFTs and neuropil thread densities were significantly greater in DSD + compared to DSD âˆ’, while striatal NFT densities were similar between groups. FC pS422-positive and TauC3 NFT densities were significantly greater than Alz50-labeled NFTs in DSD + , but not DSD âˆ’ cases. Putaminal, but not caudate pS422-positive NFT density, was significantly greater than TauC3-positive NFTs. In the FC, AT8 + pS422 + Alz50, TauC3 + pS422 + Alz50, pS422 + Alz50, and TauC3 + pS422 positive NFTs were more frequent in DSD + compared to DSD- cases. Single gene-array profiling of FC pS422 positive neurons revealed downregulation of 63 of a total of 864 transcripts related to AÎ²/tau biology, glutamatergic, cholinergic, and monoaminergic metabolism, intracellular signaling, cell homeostasis, and cell death in DSD + compared DSD âˆ’ cases. These observations suggest that abnormal tau aggregation plays a critical role in the development of dementia in DS.
Digital Object Identifier (DOI)
Perez, Sylvia E.; Miguel, Jennifer C.; He, Bin; Malek-Ahmadi, Michael; Abrahamson, Eric E.; Ikonomovic, Milos D.; Lott, Ira; Doran, Eric; Alldred, Melissa J.; Ginsberg, Stephen D.; and Mufson, Elliott J., "Frontal Cortex And Striatal Cellular And Molecular Pathobiology In Individuals With Down Syndrome With And Without Dementia" (2019). Neurobiology. 320.