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O4‐03‐02: Activated astrocytes suppress amyloid plaque pathogenesis in APP/PS1 mice
Author(s) -
Kraft Andrew W.,
Hu Xiaoyan,
Yan Ping,
Xiao Qingli,
Holmes Brandon B.,
Wilhelmsson Ulrika,
Cirrito John R.,
Holtzman David M.,
Pekny Milos,
Lee JinMoo
Publication year - 2009
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.2009.05.532
Subject(s) - pathogenesis , microglia , astrocytosis , astrocyte , gliosis , glial fibrillary acidic protein , pathology , vimentin , senile plaques , inflammation , amyloid precursor protein , neuroinflammation , biology , microbiology and biotechnology , immunology , medicine , immunohistochemistry , alzheimer's disease , neuroscience , disease , central nervous system
of conformationally abnormal and hyperphosphorylated tau. The presence of NFT in the neocortex is associated with impairments of cognitive function, supporting a central role for tau in dementia. The significance of the accumulation of NFT for neuronal and cognitive function is still obscure. Objective (s): To investigate whether tau accumulation and aggregation is involved in inducing cognitive impairments by affecting synaptic function, we studied synaptic and cognitive functions of the htau mouse. The hTau mouse develops tau pathology similar to observed in AD in its distribution and its age-dependent development. Methods: Animals: htau mice and agematched wild type mice: male (C57BL/6 J) ages 4 and 12 months. Electrophysiology: extracellular field excitatory postsynaptic potentials (EPSPs) evoked at the CA3-CA1 synapse were recorded to assess basal synaptic transmission (input-output curve and paired pulse facilitation) and long term potentiation (LTP). Behavior: visual recognition memory was measured by an object recognition memory test that measured spontaneous preference for a novel object compared to a familiar object. The spatial memory was assessed by the Morris water maze test (MWM). Results: Htau mice develop age-dependent cognitive and physiological impairments. 4 months-old htau mice, with early stage of tau pathology (pre-tangles) are unaffected behaviorally and physiologically. Concurrent with the development of moderate tau pathology in the forebrain, 12 months-old htau mice develop learning and memory deficits. 12 months-old htau mice show cognitive deficits in object recognition and spatial memories which are associated with cortical and hippocampal dysfunction, precisely the brain regions affected by tau pathology. Basal synaptic transmission and induction of LTP with high frequency stimulation (HFS), but not theta burst stimulation, are perturbed in hippocampal CA1 region of old but not young htau mice. In addition, at 12 months htau mice had diminished charge transfer during HFS as a result of the inability of Schaffer collateral fibers to sustain high frequency activity. Conclusions: Our results suggest that tau pathology may underlie an age-dependent learning impairment through disruption of synaptic function.