Type-I interferon pathway in neuroinflammation and neurodegeneration: focus on Alzheimer's disease.

Past research in Alzheimer's disease (AD) has largely been driven by the amyloid hypothesis; the accompanying neuroinflammation seen in AD has been assumed to be consequential and not disease modifying or causative. However, recent data from both clinical and preclinical studies have established that the immune-driven neuroinflammation contributes to AD pathology. Key evidence for the involvement of neuroinflammation in AD includes enhanced microglial and astroglial activation in the brains of AD patients, increased pro-inflammatory cytokine burden in AD brains, and epidemiological evidence that chronic non-steroidal anti-inflammatory drug use prior to disease onset leads to a lower incidence of AD. Identifying critical mediators controlling this neuroinflammation will prove beneficial in developing anti-inflammatory therapies for the treatment of AD. The type-I interferons (IFNs) are pleiotropic cytokines that control pro-inflammatory cytokine secretion and are master regulators of the innate immune response that impact on disorders of the central nervous system. This review provides evidence that the type-I IFNs play a critical role in the exacerbation of neuroinflammation and actively contribute to the progression of AD.

The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. Deposition of amyloid-ß (Aß) remains a hallmark feature of the disease, yet the precise mechanism(s) by which this peptide induces neurotoxicity remain unknown. Neuroinflammation has long been implicated in AD pathology, yet its contribution to disease progression is still not understood. Recent evidence suggests that various Aß complexes interact with microglial and astrocytic expressed pattern recognition receptors that initiate innate immunity. This process involves secretion of pro-inflammatory cytokines, chemokines and generation of reactive oxygen species that, in excess, drive a dysregulated immune response that contributes to neurodegeneration. The mechanisms by which a neuroinflammatory response can influence Aß production, aggregation and eventual clearance are now becoming key areas where future therapeutic intervention may slow progression of AD. This review will focus on evidence supporting the combined neuroinflammatory-amyloid hypothesis for pathogenesis of AD, describing the key cell types, pathways and mediators involved. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Deposition of intracellular plaques containing amyloid-beta (Aß) is a hallmark proteinopathy of the disease yet the precise mechanisms by which this peptide induces neurotoxicity remains unknown. A neuroinflammatory response involving polarized microglial activity, enhanced astrocyte reactivity and elevated pro-inflammatory cytokine and chemokine load has long been implicated in AD and proposed to facilitate neurodegeneration. In this issue we discuss key receptor systems of innate immunity that detect Aß, drive pro-inflammatory cytokine and chemokine production and influence Aß aggregation and clearance. Evidence summarized in this review supports the combined neuroinflammatory-amyloid hypothesis for pathogenesis of AD and highlights the potential of immunomodulatory agents as potential future therapies for AD patients.

Microbial Immuno-Communication in Neurodegenerative Diseases.

Neuro-inflammation is a critical process by which the brain coordinates chemokine-regulated cellular recruitment, cytokine release, and cell-mediated removal of pathogenic material to protect against infection or brain injury. Dysregulation of this immune response is involved in multiple neurodegenerative disorders, however the precise contribution of neuro-inflammation to the exacerbation and progression of these diseases remains unclear. Evidence now suggests that commensal micro-organisms populating the host and their metabolites, collectively termed the microbiome, regulate innate immunity by influencing peripheral immune cell populations, and modulating microglial phenotype. Recent preclinical studies now demonstrate that perturbations in the host microbiome can induce alterations in pathological phenotypes associated with numerous neurodegenerative diseases. How perturbations in the host microbiome and subsequently altered peripheral immune status are communicated to the brain to influence neuro-inflammatory processes in these neurodegenerative disease settings is far from understood. This review provides insight into the regulation of neuro-inflammatory processes by the host microbiome in the context of neurodegenerative disease and highlights the potential importance of the blood-brain barrier and blood-cerebrospinal fluid-brain barrier, functioning as "immune barriers," to communicate host immune status to the brain. Understanding the mechanisms by which the commensal microbiome communicates with the brain to influence neuro-inflammatory processes will be critical in the development of microbially-targeted therapeutics in the potential treatment of neurodegenerative disorders.

Cell-targetable DNA nanocapsules for spatiotemporal release of caged bioactive small molecules.

Achieving triggered release of small molecules with spatial and temporal precision at designated cells within an organism remains a challenge. By combining a cell-targetable, icosahedral DNA-nanocapsule loaded with photoresponsive polymers, we show cytosolic delivery of small molecules with the spatial resolution of single endosomes in specific cells in Caenorhabditis elegans. Our technology can report on the extent of small molecules released after photoactivation as well as pinpoint the location at which uncaging of the molecules occurred. We apply this technology to release dehydroepiandrosterone (DHEA), a neurosteroid that promotes neurogenesis and neuron survival, and determined the timescale of neuronal activation by DHEA, using light-induced release of DHEA from targeted DNA nanocapsules. Importantly, sequestration inside the DNA capsule prevents photocaged DHEA from activating neurons prematurely. Our methodology can in principle be generalized to diverse neurostimulatory molecules.

Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1ΔE9 murine model of Alzheimer's disease.

Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer's disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APPSWE/PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-ß (Aß) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE/PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aß deposition in aged APPSWE/PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.

Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype.

A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood. Type-1 interferons (IFNs) are master regulators of innate immunity and have been implicated in multiple CNS disorders, however their role in AD progression has not yet been fully investigated. Hence, we generated APPSWE/PS1ΔE9 mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APPSWE/PS1ΔE9 x IFNAR1(-/-)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APPSWE/PS1ΔE9 x IFNAR1(-/-) mice displayed a modest reduction in Aß monomer levels, despite maintenance of plaque deposition. This finding correlated with partial rescue of spatial learning and memory impairments in the Morris water maze in comparison to APPSWE/PS1ΔE9 mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice compared to APPSWE/PS1ΔE9 mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice in comparison to APPSWE/PS1ΔE9 mice. These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aß1-42 treatment of IFNAR1(-/-) primary glial cultures. Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.

Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease.

Severe amyloidosis and plaque-localized neuro-inflammation are key pathological features of Alzheimer's disease (AD). In addition to astrocyte and microglial reactivity, emerging evidence suggests a role of gut microbiota in regulating innate immunity and influencing brain function. Here, we examine the role of the host microbiome in regulating amyloidosis in the APPSWE/PS1ΔE9 mouse model of AD. We show that prolonged shifts in gut microbial composition and diversity induced by long-term broad-spectrum combinatorial antibiotic treatment regime decreases Aß plaque deposition. We also show that levels of soluble Aß are elevated and that levels of circulating cytokine and chemokine signatures are altered in this setting. Finally, we observe attenuated plaque-localised glial reactivity in these mice and significantly altered microglial morphology. These findings suggest the gut microbiota community diversity can regulate host innate immunity mechanisms that impact Aß amyloidosis.

Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer's disease.

A neuro-inflammatory response has been implicated in human patients and animal models of Alzheimer's disease (AD). Type-1 interferons are pleiotropic cytokines involved in the initiation and regulation of the pro-inflammatory response; however, their role in AD is unknown. This study investigated the contribution of type-1 IFN signaling in the neuro-inflammatory response to amyloid-beta (Aß) in vitro and in the APP/PS1 transgenic mouse model of AD. Enzyme-linked immunosorbent assay confirmed a 2-fold increase in IFNα in APP/PS1 brains compared with control brains. Quantitative polymerase chain reaction also identified increased IFNα and IFNß expression in human pre-frontal cortex from AD patients. In vitro studies in primary neurons demonstrated Aß-induced type-1 IFN expression preceded that of other classical pro-inflammatory cytokines, IL1-ß, and IL-6. Significantly, ablation of type-1 interferon-α receptor 1 expression in BE(2)M17 neuroblastoma cells and primary neurons afforded protection against Aß-induced toxicity. This study supports a role for type-1 interferons in the pro-inflammatory response and neuronal cell death in AD and suggests that blocking type-1 interferon-α receptor 1 maybe a therapeutic target to limit the disease progression.

Nanofibrous scaffolds releasing a small molecule BDNF-mimetic for the re-direction of endogenous neuroblast migration in the brain.

Brain tissue engineering has the potential to harness existing elements of neurogenesis within the adult brain to overcome a microenvironment that is otherwise inhibitory to regeneration, especially following severe tissue damage. This study investigates the ability of electrospun poly ε-caprolactone (PCL) to re-direct the migratory pathway of endogenous neuroblasts from the disrupted subventricular zone (SVZ). A small molecule non-peptide ligand (BDNF-mimetic) that mimicked the trophic properties of brain-derived neurotrophic factor (BDNF) was incorporated into electrospun PCL scaffolds to improve neuroblast survival and promote neuroblast migration towards the implant. PCL scaffolds were able to support neuroblast infiltration and migration along the implant tract. In the presence of the BDNF-mimetic, neuroblasts were able to migrate towards the implant via the parenchyma, and their persistence within the implants was prolonged. In addition, the BDNF-mimetic improved implant integration and increased local neuronal plasticity by increasing neurite sprouting at the tissue-implant interface. SMI32+ neurites were observed inside scaffolds at 21 days but not 8 days post implantation, indicating that at least some of the infiltrated neuroblasts had differentiated into neurons.