Dickson, Dennis W

Abstract Reactive gliosis surrounding amyloid β (Aβ) plaques is an early feature of Alzheimer’s disease pathogenesis and has been postulated to represent activation of the innate immune system in an apparently ineffective attempt to clear or neutralize Aβ aggregates. To evaluate the role of IFN-γ–mediated neuroinflammation on the evolution of Aβ pathology in transgenic (Tg) mice, we have expressed murine IFN-γ (mIFN-γ) in the brains of Aβ precursor protein (APP) Tg mice using recombinant adeno-associated virus serotype 1. Expression of mIFN-γ in brains of APP TgCRND8 mice results in robust noncell autonomous activation of microglia and astrocytes, and a concomitant significant suppression of Aβ deposition. In these mice, mIFN-γ expression upregulated multiple glial activation markers, early components of the complement cascade as well as led to infiltration of Ly-6c positive peripheral monocytes but no significant effects on APP levels, APP processing or steady-state Aβ levels were noticed in vivo. Taken together, these results suggest that mIFN-γ expression in the brain suppresses Aβ accumulation through synergistic effects of activated glia and components of the innate immune system that enhance Aβ aggregate phagocytosis.

Proinflammatory stimuli, after amyloid β (Aβ) deposition, have been hypothesized to create a self‐reinforcing positive feedback loop that increases amyloidogenic processing of the Aβ precursor protein (APP), promoting further Aβ accumulation and neuroinflammation in Alzheimer's disease (AD). Interleukin‐6 (IL‐6), a proinflammatory cytokine, has been shown to be increased in AD patients implying a pathological interaction. To assess the effects of IL‐6 on Aβ deposition and APP processing in vivo ,we overexpressed murine IL‐6 (mIL‐6) in the brains of APP transgenic TgCRND8 and TG2576 mice. mIL‐6 expression resulted in extensive gliosis and concurrently attenuated Aβ deposition in TgCRND8 mouse brains. This was accompanied by up‐regulation of glial phagocytic markers in vivo and resulted in enhanced microglia‐mediated phagocytosis of Aβ aggregates in vitro . Further, mIL‐6‐induced neuroinflammation had no effect on APP processing in TgCRND8 and had no effect on APP processing or steady‐state levels of Aβ in young Tg2576 mice. These results indicate that mIL‐6‐mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing Aβ plaque clearance rather than mediating a neurotoxic feedback loop that exacerbates amyloid pathology. This is the first study that methodically dissects the contribution of mIL‐6 with regard to its potential role in modulating Aβ deposition in vivo .—Chakrabarty, P., Jansen‐West, K., Beccard, A., Ceballos‐Diaz, C., Levites, Y., Verbeeck, C., Zubair, A. C., Dickson, D., Golde, T. E., Das, P. Massive gliosis induced by interleukin‐6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J . 24, 548–559 (2010). www.fasebj.org

Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a ≈25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.

Alzheimer's disease and other tauopa‐thies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer's disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long‐term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points—during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho‐tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho‐tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia‐induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.— Planel, E.,Bretteville, A., Liu, L., Virag, L., Du, A. L., Yu, W. Y., Dickson, D. W., Whittington, R. A., Duff, K. E. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. FASEBJ. 23, 2595–2604 (2009)