Background: Beta amyloid (Aβ) peptides are the major constituents of the senile plaques present in Alzheimer's diseased brain. Pathogenesis has been associated with the aggregated form of the peptide as these fibrils are the conformation readily found in the plaques. However, recent studies have shown that the nonaggregated, soluble assemblies of Aβ have the potential to stimulate neuronal dysfunction and may play a prominent role in the pathogenesis of Alzheimer's disease.

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Alzheimer’s disease (AD) has been well characterized by the presence of reactive microglia, often associated with Aβ-plaque deposition. The oligomeric form of Aβ peptide (Aβo) has neurotoxic effects in the presence of microglia and is suggested to potentiate proinflammatory changes in microglia in AD. Primary murine microglia cultures stimulated with Aβo displayed increased protein phospho-tyrosine and secreted TNF-α levels which were attenuated by the Src/Abl inhibitor, dasatinib. Intracerebroventricular infusions of Aβo into C57BL6/J mice stimulated increased microgliosis and protein phospho-tyrosine levels that were also attenuated by dasatinib administration. The rodent findings were validated in human AD brains versus age-matched controls demonstrating reactive microglial association with Aβo deposits and increased microglial protein phospho-tyrosine and phospho-Src levels. These data suggest a role for Aβo in microglial activation through a tyrosine kinase-dependant pathway both in rodent models and human disease. Use of a selective non-receptor tyrosine kinase inhibitor such as dasatinib to attenuate microglial-dependent proinflammatory changes may prove to be an important step towards developing anti-inflammatory treatments for AD.

Background Microglial activation is an important histologic characteristic of the pathology of Alzheimer’s disease (AD). One hypothesis is that amyloid beta (Aβ) peptide serves as a specific stimulus for tyrosine kinase-based microglial activation leading to pro-inflammatory changes that contribute to disease. Therefore, inhibiting Aβ stimulation of microglia may prove to be an important therapeutic strategy for AD. Methods Primary murine microglia cultures and the murine microglia cell line, BV2, were used for stimulation with fibrillar Aβ1-42. The non-receptor tyrosine kinase inhibitor, dasatinib, was used to treat the cells to determine whether Src family kinase activity was required for the Aβ stimulated signaling response and subsequent increase in TNFα secretion using Western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. A histologic longitudinal analysis was performed using an AD transgenic mouse model, APP/PS1, to determine an age at which microglial protein tyrosine kinase levels increased in order to administer dasatinib via mini osmotic pump diffusion. Effects of dasatinib administration on microglial and astroglial activation, protein phosphotyrosine levels, active Src kinase levels, Aβ plaque deposition, and spatial working memory were assessed via immunohistochemistry, Western blot, and T maze analysis. Results Aβ fibrils stimulated primary murine microglia via a tyrosine kinase pathway involving Src kinase that was attenuated by dasatinib. Dasatinib administration to APP/PS1 mice decreased protein phosphotyrosine, active Src, reactive microglia, and TNFα levels in the hippocampus and temporal cortex. The drug had no effect on GFAP levels, Aβ plaque load, or the related tyrosine kinase, Lyn. These anti-inflammatory changes correlated with improved performance on the T maze test in dasatinib infused animals compared to control animals. Conclusions These data suggest that amyloid dependent microgliosis may be Src kinase dependent in vitro and in vivo. This study defines a role for Src kinase in the microgliosis characteristic of diseased brains and suggests that particular tyrosine kinase inhibition may be a valid anti-inflammatory approach to disease. Dasatinib is an FDA-approved drug for treating chronic myeloid leukemia cancer with a reported ability to cross the blood-brain barrier. Therefore, this suggests a novel use for this drug as well as similar acting molecules.