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P1‐094: EXPLORING POTENTIAL TARGETS OF AD PATHOLOGY: NANOMEDICINE USING INTRANASAL ROUTE IN A TRANSGENIC MODEL OF AD‐LIKE AMYLOID PATHOLOGY
Author(s) -
Navas Maria Eugenia,
Bruno Martin Alejandro,
Mestre Maria Belen
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.05.330
Subject(s) - neuroinflammation , microglia , genetically modified mouse , nasal administration , pharmacology , transgene , neuroscience , medicine , chemistry , biology , immunology , inflammation , biochemistry , gene
Background: The role of the neuroinflammatory cells in Alzheimer’s disease (AD) and the functional changes of microglia during disease progression are still unknown. Chronic inflammation with activated microglia could mediate neuronal damage and death by producing toxic products, leading to a cascade of harmful pathogenic events. However, the microglial phenotypes in the human pathology have not been determined yet. Therefore, here we examined the microglial phenotypic changes, the expression of proinflammatory cytokines and neurodegeneration during the course of AD in the human hippocampus. Methods: RT-PCR, western blots and immunohistochemistry were performed in hippocampal samples from human autopsies of non-demented controls and clinically diagnosed mild (Braak II), moderate (Braak III-IV) and severe (Braak V-VI) AD cases. Results: Microglial cells from Braak V/VI samples displayed a classic differentiation state by expression of M1 markers. However, microglial cells from dentate gyrus showed a degenerative morphology with fragmented and dystrophic processes. Moreover, the stereological quantification of dentate gyrus positive-Iba1 population showed a slight decrease compared to mild AD stages and controls. This senescent environment was coincident with a significant decline of the neuronal markers somatostatin (SOM), neuropeptide Y (NPY) and parvalbumin (PV). Numerous and huge APP, tau and SOM-positive dystrophyc neurites were observed along this neurodegenerative state. Finally, both soluble amyloid and tau forms from the whole hippocampus of severe patients induced the activation of microglial cells to a classic phenotype expressing TNF-alpha. Conclusions: Although it remains unclear whether inflammation represents a cause or consequence of AD, the presence of different Abeta/tau soluble forms could trigger this microglial dysfunction/impairment. Loss of neuroprotection by microglial cells in this highly vulnerable region, could account for the GABAergic interneurons degeneration observed in the severe stages of AD patients. Supported by FIS-PI12/01431 (AG), FIS-PI12/01439 (JV).