Krikor Dikranian and D H Holzman
Scientific Tracks Abstracts: J Neurol Neurophysiol
Electron microscopy (EM) has made important contributions in understanding of the structural components of the diffuse and fibrillar amyloid plaques. Neurofibrillary tangles formed by hyperphosphorylated tau (paired helical filaments) have been extensively studied in degenerating neurons by transmission electron microscopy as well as by scanning electron microcopy. A strong correlation with cognitive decline in Alzheimer?s disease (AD) is believed to be accompanied with age- dependent axonal degeneration and progressive loss of synapses. Ultrastructural studies in humans with AD have characterized the morphology of tau and non-tau related neuritic dystrophy and have quantified synapse loss. Animal models of AD-type brain degeneration have provided excellent opportunities to study amyloid and neuritic pathology in detail. Here we show results from our detailed EM analysis of axonal degeneration and cell dystrophy in the cortex and hippocampus of various transgenic mouse models of different aspects of AD-like pathology (PDAPP, APP/PS1, APP/PS1 mice expressing human apolipoprotein E isoforms, and P301S Tau transgenic mice overexpressing a mutant form of Tau). All transgenic mice shared common pathological changes observed as early as the second postnatal month. These included robust axonal degeneration, synapse dystrophy and sporadic cell death of the non-apoptotic nature. In P301S Tau transgenic mice specifically, axonal swelling and degeneration was accompanied by axoplasmic accumulation of a dense filamentous network (20 nm in diameter). Neuronal degeneration was more robust and was characterized by cytoplasmic accumulation of filaments and autophagic vacuoles. The majority of dystrophic cells exhibited signs of non-apoptotic cell death although apoptotic cell death morphology was also observed. In the neuropil of P301S Tau transgenic mouse brains, characteristic activation of astroglial cells with cell processes filled with densely packed intermediate filaments was frequently encountered especially in areas of axonal degeneration. Taken together our EM studies suggest that compared to PDAPP, APP/PS1 and APP/PS1/ApoE transgenic mice, the process of neuronal cell and axonal degeneration in P301S Tau transgenic animals shows some unique morphologic features and robust involvement of astroglia.
Krikor Dikranian is an Associate Professor of the Department of Anatomy & Neurobiology in Washington University, USA. He received his MD from Medical University, Varna, Bulgaria in 1978 & PhD from Medical Academy, Sofia, Bulgaria in 1992. he have extensively studied the morphology of the vascular and nervous systems including the enteric nervous system. In the last 15 years the focus of his scientific interest has been the pathomorphology of the central and peripheral nervous systems. he has performed morphological studies in this system in close collaboration with the departments of Psychiatry, Neurology, Ophthalmology, Cell Biology and Biomedical Engineering. In ongoing projects with the Department of Neurology he was studying the development of neuronal and axonal changes after brain trauma and in transgenic mice expressing mutations common in Alzheimer?s disease. Mapping the human macro-connectome represents a grand challenge for the coming century and the field of connectomics received a major boost with the launching of the Human Connectome Project (HCP) in 2010. This is a large- scale NIH-sponsored effort to map the human connectome in healthy adults. A very big portion of this project is performed in the Department of Anatomy and Neurobiology at Washington University School of Medicine in Saint Louis under the leadership of David van Essen, one of the Principal Investigators. Diffusion imaging and resting-state fMRI represent the two main modalities for examining the macro-connectome in vivo. his contribution to the project relates to combining and navigating MRI data with data from histological studies on primates by tracking trajectories of axonal pathways between the white matter and gray matter.
