Kevin R. Doty

Innate Immunity Fights Alzheimer's Disease

Alzheimers disease (AD) is the most common age-related dementia. Pathognomonic accumulation of cerebral β-amyloid plaques likely results from imbalanced production and removal of amyloid-β (Aβ) peptides. In AD, innate immune cells lose their ability to restrict cerebral Aβ accumulation. At least in principle, mononuclear phagocytes can be enlisted to clear Aβ/β-amyloid from the brain. While the classical focus has been on dampening neuroinflammation in the context of AD, we hypothesize that rebalancing cerebral innate immunity by inhibiting actions of key anti-inflammatory cytokines returns the brain to a physiological state. Recent experiments demonstrating beneficial effects of blocking anti-inflammatory cytokine signaling in preclinical mouse models provide supportive evidence. This concept represents an important step toward innate immune-targeted therapy to combat AD.

The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?

Neurodegenerative diseases share common features, including catastrophic neuronal loss that leads to cognitive or motor dysfunction. Neuronal injury occurs in an inflammatory milieu that is populated by resident and sometimes, infiltrating, immune cells - all of which participate in a complex interplay between secreted inflammatory modulators and activated immune cell surface receptors. The importance of these immunomodulators is highlighted by the number of immune factors that have been associated with increased risk of neurodegeneration in recent genome-wide association studies. One of the more difficult tasks for designing therapeutic strategies for immune modulation against neurodegenerative diseases is teasing apart beneficial from harmful signals. In this regard, learning more about the immune components of these diseases has yielded common themes. These unifying concepts should eventually enable immune-based therapeutics for treatment of Alzheimer׳s and Parkinson׳s diseases and amyotrophic lateral sclerosis. Targeted immune modulation should be possible to temper maladaptive factors, enabling beneficial immune responses in the context of neurodegenerative diseases. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

STAT3 SIGNALING REFEREES MICROGLIAL AMYLOID CLEARANCE IN ALZHEIMER’S DISEASE

tion in the Golgi and also shows greatly impaired cell surface expression. Surprisingly, we find that these mutants appear to be exported from the endoplasmic reticulum (ER) without defect. The results suggest the existence of an efficient protein recycling pathway that returns mutant TREM2 to the ER after export. Intriguingly, we find that all mutants that fail to undergo maturation also display a propensity to form a stable homodimer that is not dissociated by SDS, urea, reducing agents or heating. Because all mutations producing this effect localize to the extracellular, Ig-like domain, the results suggest an important role for this domain in regulating the biochemical characteristics of TREM2. Conclusions: Our findings suggest that disease-causing TREM2 mutations may result in early-onset neurodegeneration via loss of cell surface expression, and imply that a common biochemical abnormality is induced by pathogenic mutations within the Ig-like domain.

PHYSICAL INTERACTION OF TREM2 AND C1Q IN ALZHEIMER’S DISEASE

mice were analyzed for tau pathology. Results:TREM2-targeted ASO treatment in APP/PS1 mice substantially decreased TREM2 mRNA compared to control ASO treatment across multiple brain regions (p<0.01). When evaluated for Ab, ASO-mediated TREM2 knockdown significantly reduced Ab plaque deposition (p<0.001) and attenuated microglial association around plaque deposits (p<0.001). Treatment of TauP301S mice with TREM2-targeted ASO robustly decreased TREM2mRNA (p<0.001) and was associated with significantly less phosphorylated tau reactivity within the hippocampus (p<0.05). Conclusions: These results confirm a role for TREM2 in mediating plaque deposition and tau phosphorylation and suggest that TREM2 lowering reduces pathological markers of neurodegeneration. While these data are seemingly contradictory to the presumption that TREM2 genetic variants confer a loss of function, we believe an ASO approach allows us to understand the timing of TREM2 action throughout disease progression, which may involve a timeor location-dependent role for TREM2. Overall, ASOs that target TREM2 will be highly informative on TREM2-mediated AD pathogenesis and may be effective at modulating disease.

IRAK-M PROMOTES MICROGLIAL Aβ TOLERANCE BY ACTIVATING ALTERNATIVE NF-KB SIGNALING

Testosterone deprivation aggravated cognitive dysfunction in obese-insulin resistant rats. Testosterone deprivation aggravated cognitive decline as indicated by increasing time to teach plattorm (A) and decreasing time in target quadrant (B). High fat consumption and testosterone deprivation increased hippocampal ROS production (C) and increased hippocampal apoptosis as indicated by increasing number cortical TUNEL positive cells (D). Testosterone deprivation exacerbated glia morphological changed as indicated by increasing microglial volume (E) and astrocyte volume (F). NDS; ND-fed rats with sham operation, NDO; ND-fed rats with orchiectomy, HFS; HFD-fed rats with sham operation, HFO; HFD-fed rats with orchiectomy (N1⁄46 of each group). *p<0.05 in comparison with NDS, yp<0.05 in comparison with HFS, zp<0.05 in comparison with NDO.

Il10 deficiency licenses innate immunity to fight against cerebral amyloidosis

alpha-synuclein fibrils, rAAVmediated expression of IL-10, a master anti-inflammatory cytokine, suppresses proinflammatory chemokine, cytokine and other innate immune factor gene induction. Based on this data that IL-10, an anti-inflammatory cytokine, markedly dampens innate immune activation in vitro, we postulated that IL-10 based therapies may have beneficial outcome in aS mouse models. Methods:We have tested the effect of spinal cord targeted delivery of rAAV-IL-10 in the homozygous M83 mice expressing the A53Tmutant alpha synuclein. An additional ‘seeded’ model using the peripheral to central propagation of aS pathology in hemizygous M83 mice was also used (See, Sacino et al, Proc Natl

HARNESSING INNATE IMMUNITY TO TREAT ALZHEIMER'S DISEASE

Background: Generation of neurotoxic amyloid-ß peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer’s disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction actively contributes to disease progression and chronicity. Microglia is being activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors which elicit an innate immune response. The latter is characterized by the release of in€ıflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and enzyme systems. Exogenous as well as endogenous factors may promote and facilitate neuroinflammation in the AD brain. Thus, degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may drive inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. Methods: Analysis of neuroinflammatio and in particular of micro and astroglial cell function in vitro and in vivo. Determination of inflammatory markes from cell culture, murine mouse brain and brain tissue or cerebrospinal fluid of MCI and AD patients. Results: In inflammation may not just occur secondary to degeneration, but actively drive amyloid beta aggregation and APP processing. Inhibition of themicroglia driven innate immune response at key signalling steps may provide protection. Conclusions: Therefore, antiinflammatory treatment strategies should be considered. Data on microglial activation in AD along with suggestions to modify and alter the prointo an antiinflammatory phenotype will be reviewed and discussed.