Glia-driven neurodegeneration and neurorepair in age-related dementias

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Daniela Durand

INBIOMED Instituto de Investigaciones Biomédicas UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires

Carla Caruso

INBIOMED Instituto de Investigaciones Biomédicas UBA-CONICET, School of Medicine, University of Buenos Aires

Although brain aging is accompanied by molecular and synaptic changes, dementias develop with particular hallmarks and lead to impairment in routine memory, skills, and knowledge, affecting daily activities and autonomy. Our knowledge on age-related dementias has grown and diverged from specific protein malfunction to multifactorial components, including glial dysfunction and neuroinflammation. However, it is still debated whether glial dysfunction is an initial step in the cascade of neurodegenerative events in these diseases or if glia is just exacerbating damage after triggering neuroinflammatory pathways. A diversity of disease models can help address these issues. This symposium aimed at collecting significant evidence to reconsider the pathophysiology of age-related neurodegenerative diseases with focus on glial alterations. Consequently, glial cells can be presented as target for disease-modifying therapeutics.

Heterogeneity of microglial activation states in Alzheimer Disease

Suman Jayadev

University of Washington

Microglia-mediated neuroinflammation contributes to disease progression in neurodegenerative diseases such as Alzheimer’s Disease (AD). Microglia subtypes are complex, with beneficial and harmful phenotypes. Understanding the gene expression networks which define the spectrum of microglia phenotypes is critical to identifying specific targets for neuroinflammation modulating therapies. We studied post-mortem brain tissue from 22 total individuals, 12 of whom had significant AD neuropathic change. Nuclei isolated from prefrontal cortex were sorted for the myeloid marker PU.1 using fluorescence activated nucleus sorting (FANS) and sequenced with the 10X Genomics Chromium platform. Unbiased clustering revealed 10 microglia clusters we could then annotate based on differential gene expression and pathway analysis. We found a diversity in the various “activation” microglia subtypes, a few of which were either over or under-represented by AD nuclei compared to controls. Trajectory analysis can also reveal differential “paths” taken by AD and control nuclei from inactivated to activated. Our efforts contribute to ongoing efforts in more precise microglia phenotyping for the purpose of tailored neuroimmune therapeutics.

Age-related changes on the activation of microglia promotes neuroinflammation and neuron damage

Rommy von Bernhardi

Facultad de Ciencias de la Salud. Universidad San Sebastian

Our glia-dysregulation hypothesis states that AD is caused by impaired microglia (MG) leading to neuronal dysfunction & neurodegeneration. Aged MG show increased inflammation. Compared with 3 m-old mice, scavenger receptor-A (SRA) is reduced in 12 m-old WT mice, as was already observed in young APP/PS1 mice. SRA is involved in β-amyloid (Aβ) uptake and the inflammatory activation of glia, we compared the activation of MG obtained from WT, SRA-/- & APP/PS1/SRA-/- mice, to assess age-dependent activation, cytokines, and MAPK signal. We assessed cytokine levels by ELISA, and the activation of signaling pathways by WB. The neurotoxicity of activated MG conditioned media (CMs) MG was evaluated on hippocampal neurons by TUNEL. Glia from SRA-/- and triple mice had levels of TNFα & IL1β 7-fold higher, and anti-inflammatory cytokines (IL10 & TGFβ) several-fold lower than WT glia. SRA-/- cells showed complex changes in the activation of signaling pathways and the release of cytokines in response to inflammatory stimulation. CMs of basal MG from SRA-/- mice were more neurotoxic than that of WT mice. SRA-/- MG stimulated with LPS were less neurotoxic that WT cells, whereas Aβ and Aβ+LPS-stimulated MG induction of hippocampal neurons apoptosis was similar for all the genotypes. Our results show that the inflammatory activation results in reduced cytotoxicity in SRA-/- mice, whereas activation by Aβ is preserved. SRA appears to participate in a complex regulation of the activation of MG.

Late neurological consequences of early life infections: the role of microglia

Julia Clarke

Federal University of Rio de Janeiro

Harmful environmental stimuli during critical stages of development can profoundly affect behavior and susceptibility to diseases. Alzheimer disease (AD) is the most frequent neurodegenerative disease, and evidence suggest that inflammatory conditions act cumulatively, contributing to disease onset. Here we investigated whether infection early in life can contribute to synapse damage and cognitive impairment induced by amyloid-β oligomers (AβOs), neurotoxins found in AD brains. To this end, wild-type mice were subjected to neonatal (post-natal day 4) infection by Escherichia coli (1 × 104 CFU/g), the main cause of infection in low-birth-weight premature infants in the US. E. coli infection caused a transient inflammatory response in the mouse brain starting shortly after infection. Although infected mice performed normally in behavioral tasks in adulthood, they showed increased susceptibility to synapse damage and memory impairment induced by low doses of AβOs (1 pmol; intracerebroventricular) in the novel object recognition paradigm. Using in vitro and in vivo approaches, we show that microglial cells from E. coli-infected mice undergo exacerbated activation when exposed to low doses of AβOs. In addition, treatment of infected pups with minocycline, an antibiotic that inhibits microglial pro-inflammatory polarization, normalized microglial response to AβOs and restored normal susceptibility of mice to oligomer-induced cognitive impairment. Interestingly, mice infected with b

Modulating glial cells response in the aging brain: use of IGF1 gene therapy as a therapeutic tool

Maria Jose Bellini

Instituto de Investigaciones Bioquímicas de La Plata “Profesor Doctor Rodolfo R. Brenner” (INIBIOLP), CONICET-Facultad de Cs. Médicas-UNLP

Our research focuses on the modulation of neural cells and brain outcomes during aging process employing Insulin-like growth factor-1, which is essential for synaptic plasticity and neuronal survival. We reported some benefits of IGF-1 gene therapy (IGF1-GT). Here we explored the effects of GT in two experimental models of natural aging. First, we investigate the effect on the estrous cycle, the Kisspeptin/GnRH neurons, and microglia cells in middle-aged female rats. We demonstrate that IGF1-GT prolongs rats’ cyclicity, modulating Kisspeptin/GnRH secretion in the hypothalamus and modifying microglia cells number and reactivity. We propose to use IGF1-GT to delay reproductive senescence as a strategy for optimizing lifespan and combating aging-related health problems in women. Next, we studied the effects of IGF1-GT on microglial cells in 28 months old female rats. Aging presents a loss of brain homeostasis and chronic neuroinflammation, caused by senescent microglia. Therefore, it is of great interest to design strategies that allow modulating these glial cells’ phenotype. We implemented IGF1-GT in 28 months old female rats, focused on the study of microglia in Striatum. IGF-GT influences microglia number, phagocytic activity and transcriptomic expression. These results suggest that IGF1-GT could modulate microglia activation and induces the microenvironment to neuronal survival. Our work supports the use of IGF1-GT as a tool to treat age related neural pathologies