Allergy and Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive dementia with devastating effects for the patients and their families. The treatments available are purely symptomatic and there is need for treatment strategies aiming at the etiopathogenesis of AD. The effects of systemic inflammation on the development and/or progress of AD are not clarified. Present knowledge points towards both beneficial and detrimental effects of inflammation on AD, depending on both its timing and its nature. Allergy is associated with chronic systemic inflammatory changes, and its effects on the brain are largely unknown. Epidemiological studies have shown that allergic diseases were associated with increased risk for AD. The aim of this thesis was to investigate the effects of allergy on the normal brain and in association with AD-like pathology. In Paper I, we aimed to study whether chronic airway allergy affects the AD-related proteins amyloid precursor protein (APP) and hyperphosphorylated tau (p-tau), and the inflammatory status in the brain of naïve mice. We found that allergy increased p-tau levels in the brain, whereas levels of APP were not modified. Furthermore, the levels of immunoglobulin (Ig) G and E were significantly increased in the brain of allergic mice. The increase was not only confined to blood vessels but broadly in the brain parenchyma. We then aimed to study in Paper II the changes in gene expression induced by chronic airway allergy in the brain using microarray technology. Allergy induced changes in several inflammation-related signaling pathways. We found that the levels of insulin-degrading enzyme (IDE) and phosphorylated insulin receptor (p-IR) were decreased in the brain in response to allergy. In Paper III, we investigated the effects of chronic airway allergy on the brain in the 3xTgAD (Tg) mouse model for AD, and their background strain (Bg). The levels of IgG and IgE were also increased in the brain of Tg mice in response to allergy. Allergy increased the levels of C1q component C and interleukin-1β, decreased p-IR, and impaired the burrowing activity in Bg animals. The Tg mice showed increased levels of brain-derived neurotrophic factor and decay-accelerating factor (complement inhibitor), and decreased levels of phosphorylated p38. In paper IV, we analysed the levels of Igs and cytokines in cerebrospinal fluid (CSF) and serum obtained from patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and AD, with or without allergy. The relation of allergy to CSF biomarkers (p-tau, total (t)-tau, and β-amyloid (Aβ)) and mini-mental statement examination (MMSE) was investigated. We found that the CSF levels of IgG1 ratio, IgA and t-tau were lower in AD cases with allergy compared to those without allergy. The serum interferon γ levels were lower while MMSE scores were higher in MCI cases with allergy. In conclusion, our studies suggest that allergy may have negative effects on the normal brain but seemingly beneficial effects in the presence of AD-like pathology. It is possible that stimulation of immune responses induced by allergy may lead to beneficial effects on AD. So far, little is known regarding the association between AD and allergies and further studies are needed to clarify the impact of allergy on AD pathogenesis and progression

Microglia in Alzheimer\u27s disease

Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an activated state ). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer\u27s disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed

Circadian vulnerability of cisplatin?induced ototoxicity in the cochlea

The chemotherapeutic agent cisplatin is renowned for its ototoxic effects. While hair cells in the cochlea are established targets of cisplatin, less is known regarding the afferent synapse, which is an essential component in the faithful temporal transmission of sound. The glutamate aspartate transporter (GLAST) shields the auditory synapse from excessive glutamate release, and its loss of function increases the vulnerability to noise, salicylate, and aminoglycosides. Until now, the involvement of GLAST in cisplatin?mediated ototoxicity remains unknown. Here, we test in mice lacking GLAST the effects of a low?dose cisplatin known not to cause any detectable change in hearing thresholds. When administered at nighttime, a mild hearing loss in GLAST KO mice was found but not at daytime, revealing a potential circadian regulation of the vulnerability to cisplatin?mediated ototoxicity. We show that the auditory synapse of GLAST KO mice is more vulnerable to cisplatin administration during the active phase (nighttime) when compared to WT mice and treatment during the inactive phase (daytime). This effect was not related to the abundance of platinum compounds in the cochlea, rather cisplatin had a dose?dependent impact on cochlear clock rhythms only after treatment at nighttime suggesting that cisplatin can modulate the molecular clock. Our findings suggest that the current protocols of cisplatin administration in humans during daytime may cause a yet undetectable damage to the auditory synapse, more so in already damaged ears, and severely impact auditory sensitivity in cancer survivors

Circadian Regulation of Cochlear Sensitivity to Noise by Circulating Glucocorticoids

The cochlea possesses a robust circadian clock machinery that regulates auditory function. How the cochlear clock is influenced by the circadian system remains unknown. Here, we show that cochlear rhythms are system driven and require local Bmal1 as well as central input from the suprachiasmatic nuclei (SCN). SCN ablations disrupted the circadian expression of the core clock genes in the cochlea. Because the circadian secretion of glucocorticoids (GCs) is controlled by the SCN and GCs are known to modulate auditory function, we assessed their influence on circadian gene expression. Removal of circulating GCs by adrenalectomy (ADX) did not have a major impact on core clock gene expression in the cochlea. Rather it abolished the transcription of clock-controlled genes involved in inflammation. ADX abolished the known differential auditory sensitivity to day and night noise trauma and prevented the induction of GABA-ergic and glutamate receptors mRNA transcripts. However, these improvements were unrelated to changes at the synaptic level, suggesting other cochlear functions may be involved. Due to this circadian regulation of noise sensitivity by GCs, we evaluated the actions of the synthetic glucocorticoid dexamethasone (DEX) at different times of the day. DEX was effective in protecting from acute noise trauma only when administered during daytime, when circulating glucocorticoids are low, indicating that chronopharmacological approaches are important for obtaining optimal treatment strategies for hearing loss. GCs appear as a major regulator of the differential sensitivity to day or night noise trauma, a mechanism likely involving the circadian control of inflammatory responses

Interpenetrating gallol functionalized tissue adhesive hyaluronic acid hydrogel polarizes macrophages to an immunosuppressive phenotype

Innovative scaffold designs that modulate the local inflammatory microenvironment through favorable macrophage polarization and suppressing oxidative stress are needed for successful clinical translation of regenerative cell therapies and graft integration. We herein report derivation of a hydrazone-crosslinked gallol functionalized hyaluronic acid (HA-GA)-based hydrogel that displayed outstanding viscoelastic properties and immunomodulatory characteristics. Grafting of 6% gallol (GA) to a HA-backbone formed an interpenetrative network by promoting an additional crosslink between the gallol groups in addition to hydrazone crosslinking. This significantly enhanced the mechanical stability and displayed shear-thinning/self-healing characteristics, facilitated tissue adhesive properties to porcine tissue and also displayed radical scavenging properties, protecting encapsulated fibroblasts from peroxide challenge. The THP-1 human macrophage cell line or primary bone-marrow-derived murine macrophages cultured within HA-GA gels displayed selective polarization to a predominantly anti-inflammatory phenotype by upregulating IL4ra, IL-10, TGF-β, and TGF-βR1 expression when compared with HA-HA gels. Conversely, culturing of pro-inflammatory activated primary murine macrophages in HA-GA gels resulted in a significant reduction of pro-inflammatory TNF-α, IL-1β, SOCS3 and IL-6 marker expression, and upregulated expression of anti-inflammatory cytokines including TGF-β. Finally, when the gels were implanted subcutaneously into healthy mice, we observed infiltration of pro-inflammatory myeloid cells in HA-HA gels, while immunosuppressive phenotypes were observed within the HA-GA gels. Taken together these data suggest that HA-GA gels are an ideal injectable scaffold for viable immunotherapeutic interventions. Statement of significance Host immune response against the implanted scaffolds that are designed to deliver stem cells or therapeutic proteins in vivo significantly limits the functional outcome. For this reason, we have designed immunomodulatory injectable scaffolds that can favorably polarize the recruited macrophages and impart antioxidant properties to suppress oxidative stress. Specifically, we have tailored a hyaluronic acid-based extracellular matrix mimetic injectable scaffold that is grafted with immunomodulatory gallol moiety. Gallol functionalization of hydrogel not only enhanced the mechanical properties of the scaffold by forming an interpenetrating network but also induced antioxidant properties, tissue adhesive properties, and polarized primary murine macrophages to immunosuppressive phenotype. We believe such immunoresponsive implants will pave the way for developing the next-generation of biomaterials for regenerative medicine applications.De två första författarna delar förstaförfattarskapet</p

Myeloid cell-specific topoisomerase 1 inhibition using DNA origami mitigates neuroinflammation

Targeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Our in silico drug screening reveals topoisomerase 1 (TOP1) inhibitors as promising drug candidates for microglial modulation. We show that TOP1 is highly expressed in neuroinflammatory conditions, and TOP1 inhibition using camptothecin (CPT) and its FDA-approved analog topotecan (TPT) reduces inflammatory responses in microglia/macrophages and ameliorates neuroinflammation in vivo. Transcriptomic analyses of sorted microglia from LPS-challenged mice reveal an altered transcriptional phenotype following TPT treatment. To target myeloid cells, we design a nanosystem using β-glucan-coated DNA origami (MyloGami) loaded with TPT (TopoGami). MyloGami shows enhanced specificity to myeloid cells while preventing the degradation of the DNA origami scaffold. Myeloid-specific TOP1 inhibition using TopoGami significantly suppresses the inflammatory response in microglia and mitigates MS-like disease progression. Our findings suggest that TOP1 inhibition in myeloid cells represents a therapeutic strategy for neuroinflammatory diseases and that the myeloid-specific nanosystems we designed may also benefit the treatment of other diseases with dysfunctional myeloid cells