Cerebellar amyloid-β (Aβ) deposition in the form of neuritic plaques and Purkinje cell loss are common in certain pedigrees of familial Alzheimer's disease (FAD) mainly linked to PS1 mutations. AβPP/PS1 transgenic mice, here used as a model of FAD, show a few Aβ plaques in the molecular layer of the cerebellum at 6 months, and which increase in number with age. Motor impairment is apparent in transgenic mice aged 12 months. Combined methods have shown degenerated parallel fibers as the main component of dystrophic neurites of Aβ plaques, loss of synaptic contacts between parallel fibers and dendritic spines of Purkinje cells, and degeneration of granule cells starting at 12 months and increasing in mice 18/20 months old. In addition, abnormal mitochondria and focal loss of Purkinje and basket cells, together with occasional axonal torpedoes and increased collaterals of Purkinje cells in mice aged 18/20 months, is suggested to be a concomitant defect presumably related to soluble extracellular or intracellular Aβ. These observations demonstrate serious deterioration of the neuronal circuitry in the cerebellum of AβPP/PS1 transgenic mice, and they provide support for the interpretation of similar alterations occurring in certain pedigrees with FAD.
[Show abstract][Hide abstract] ABSTRACT: The therapeutic potential of scFv-h3D6 has recently been shown in the 3xTg-AD mice. A clear effect on amyloid β (Aβ) oligomers and certain apolipoproteins in the brain was found, but no effect was seen in the cerebellum. Here, cellular vulnerability of the 3xTg-AD cerebellum is described for the first time, together with its protection by scFv-h3D6. Neuron depletion in the DCN was regionally variable and followed a mediolateral axis of involvement that was greatest in the fastigial nucleus, lesser in the interpositus and negligible in the dentate nucleus. A sole and low intraperitoneal dose of scFv-h3D6 protected 3xTg-AD DCN neurons from death. Further studies might provide interesting information about both the potential of scFv-h3D6 as a therapeutic agent and the role of the cerebellum in AD.
[Show abstract][Hide abstract] ABSTRACT: The receptor for advanced glycation end-products (RAGE) is a multiligand membrane receptor that has been implicated in the cytotoxicity effects of β-amyloid protein (Aβ) in AD. Positive feedback mechanism of RAGE within blood-brain barrier (BBB) and/or cells inside the brain are proposed, including interaction with Aβ stimulate activation of proinflammatory cytokines, release of reactive oxygen species (ROS), which leads to neuron damage and BBB dysfunction. RAGE is the main factor mediating Aβ cytotoxicity. Attenuation of RAGE activity may inhibit Aβ from accumulation in the cerebral and prevent neurotoxicity. Furthermore, RAGE may serve as a therapeutic target for Alzheimer's disease by inhibiting pathophysiological consequences of Aβ-RAGE interaction. Tight junctions (TJ) identified as the basic structure of the BBB, and RAGE mediated Aβ cytotoxicity to the brain microvascular endothelial cells (BMEC), resulted in damaged BBB structural integrity. However, the potential mechanism is poor studied.
The International journal of neuroscience 07/2013; 124(2). DOI:10.3109/00207454.2013.825258 · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study is aimed at gaining insights into the brain site-specific proteomic senescence signature while comparing physiologically aged brains with aging-related dementia brains (for example, Alzheimer's disease (AD)). Our study of proteomic differences within the hippocampus (Hp), parietal cortex (pCx) and cerebellum (Cb) could provide conceptual insights into the molecular mechanisms involved in aging-related neurodegeneration. Using an isobaric tag for relative and absolute quantitation (iTRAQ)-based two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC-MS/MS) brain site-specific proteomic strategy, we identified 950 proteins in the Hp, pCx and Cb of AD brains. Of these proteins, 31 were significantly altered. Most of the differentially regulated proteins are involved in molecular transport, nervous system development, synaptic plasticity and apoptosis. Particularly, proteins such as Gelsolin (GSN), Tenascin-R (TNR) and AHNAK could potentially act as novel biomarkers of aging-related neurodegeneration. Importantly, our Ingenuity Pathway Analysis (IPA)-based network analysis further revealed ubiquitin C (UBC) as a pivotal protein to interact with diverse AD-associated pathophysiological molecular factors and suggests the reduced ubiquitin proteasome degradation system (UPS) as one of the causative factors of AD.
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