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Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) has been implicated in synapse failure and memory impairment in Alzheimer’s disease. Here, we show that treatment with NUsc1, a single-chain variable fragment antibody (scFv) that selectively targets AβOs, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by AβOs in mice. As a therapeutic approach for intracerebral antibody delivery, we developed an adeno-associated virus vector to drive neuronal expression of NUsc1 (AAV-NUsc1) within the brain. Transduction by AAV-NUsc1 induced NUsc1 expression and secretion in adult human brain slices, and inhibited AβO binding to neurons and AβO-induced loss of dendritic spine loss in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by AβOs and, importantly, reversed memory deficits in aged APPswe/PS1ΔE9 Alzheimer’s disease model mice. These results support the feasibility of gene-mediated immunotherapy using single-chain antibodies as a potential therapeutic approach in Alzheimer’s disease.

Alzheimer’s disease (AD) is the main cause of dementia in the elderly and is characterized by memory loss, social withdrawal and neurodegeneration, eventually leading to death. Brain inflammation has emerged as a key pathogenic mechanism in AD. We hypothesized that oxytocin, a pro-social hypothalamic neuropeptide with anti-inflammatory properties, could have therapeutic actions in AD. We investigated oxytocin production in mouse models of AD, and evaluated the therapeutic potential of intranasal oxytocin. We observed lower levels of hypothalamic oxytocin in wild-type mice following brain infusion of amyloid-β oligomers (AβOs), as well as in APP/PS1 AD model mice. Treatment of APP/PS1 mice with intranasal oxytocin reduced microglial activation and favored deposition of Aβ in dense core plaques, a potentially neuroprotective mechanism. Oxytocin further alleviated social and non-social memory impairments in APP/PS1 mice. Our findings point to oxytocin as a potential therapeutic target to reduce brain inflammation and correct memory deficits in AD.

Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields.

Almost two decades ago, the first vaccine against Alzheimer's disease (AD), the most common form of dementia, reached clinical trials ([Gilman et al., 2005][1]). Its goal was to induce an adaptive immune response against aggregated amyloid-β peptide (Aβ), a main component of Alzheimer's hallmark

Alzheimer´s disease (AD) is the main cause of dementia in the elderly. Although activation of brain insulin signaling has been shown to be neuroprotective, to preserve memory in AD models, and appears beneficial in patients, the role of insulin-like growth factor 1 (IGF1) remains incompletely understood. We found reduced active/inactive IGF1 ratio and increased IGF1R expression in postmortem hippocampal tissue from AD patients, suggesting impaired brain IGF1 signaling in AD. Active/inactive IGF-1 ratio was also reduced in the brains of mouse models of AD. We next investigated the possible protective role of IGF1 in AD models. We used a recombinant adenoviral vector, RAd-IGF1, to drive the expression of IGF1 in primary hippocampal neuronal cultures prior to exposure to AβOs, toxins that accumulate in AD brains and have been implicated in early synapse dysfunction and memory impairment. Cultures transduced with RAd-IGF1 showed decreased binding of AβOs to neurons and were protected against AβO-induced neuronal oxidative stress and loss of dendritic spines. Significantly, in vivo transduction with RAd-IGF1 blocked memory impairment caused by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Our results demonstrate altered active IGF1 and IGF1R levels in AD hippocampi, and suggest that boosting brain expression of IGF1 may comprise an approach to prevent neuronal damage and memory loss in AD. Fil: Selles, Maria Clara. Universidade Federal do Rio de Janeiro; Brasil Fil: Fortuna, Juliana T. S.. Universidade Federal do Rio de Janeiro; Brasil Fil: Zappa Villar, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina Fil: de Faria, Yasmin P. R.. Universidade Federal de Sao Paulo; Brasil Fil: Souza, Amanda S.. Universidade Federal do Rio de Janeiro; Brasil Fil: Suemoto, Claudia K.. Universidade Federal de Sao Paulo; Brasil Fil: Leite, Renata E. P.. Universidade Federal de Sao Paulo; Brasil Fil: Rodriguez, Roberta D.. Universidade Federal de Sao Paulo; Brasil Fil: Grinberg, Lea T.. Universidade Federal de Sao Paulo; Brasil. University of California; Estados Unidos Fil: Reggiani, Paula Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina Fil: Ferreira, Sergio Teixeira. Universidade Federal do Rio de Janeiro; Brasil

Microcirculatory damage is a common complication for those with vascular risk factors, such as diabetes. To resolve vascular insults, the brain's immune cells (microglia) must rapidly envelop the site of injury. Currently, it is unknown whether Type 1 diabetes, a condition associated with chronic immune system dysfunction, alters microglial responses to damage and what mechanisms are responsible. Using in vivo two-photon microscopy in adult male mice, we show that microglial envelopment of laser-induced cerebral microbleeds is diminished in a hyperglycemic mouse model of Type 1 diabetes, which could not be fully rescued with chronic insulin treatment. Microglia were important for vessel repair because reduced microglial accumulation in diabetic mice or near-complete depletion in healthy controls was associated with greater secondary leakage of the damaged vessel. Broadly suppressing inflammation with dexamethasone in diabetic mice but not healthy controls, significantly enhanced microglial responses to microbleeds and attenuated secondary vessel leakage. These enhancements were associated with changes in IFN-γ signaling because dexamethasone suppressed abnormally high levels of IFN-γ protein levels in brain and blood serum of diabetic mice. Further, blocking IFN-γ in diabetic mice with neutralizing antibodies restored normal microglial chemotaxic responses and purinoceptor P2ry12 gene expression, as well as mitigated secondary leakage. These results suggest that abnormal IFN-γ signaling disrupts microglial function in the diabetic brain, and that immunotherapies targeting IFN-γ can stimulate microglial repair of damaged vessels. SIGNIFICANCE STATEMENT Although Type 1 diabetes is an established risk factor for vascular complications, such as microbleeds, and is known to hinder wound healing in the body, no study has examined how diabetes impacts the brain's innate immune reparative response (involving cells called microglia) to vascular injury. Here we show that microglial responses to brain microbleeds were diminished in diabetic animals, which also exacerbated secondary leakage from damaged vessels. These impairments were related to abnormally high levels of the proinflammatory cytokine IFN-γ because reducing IFN-γ with immunosuppressant drugs or blocking antibodies helped restore normal microglial responses and repair of damaged vessels. These data highlight the use of IFN-γ modulating therapeutics to enhance vascular repair in at-risk populations.

Made available in DSpace on 2018-11-26T22:40:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-09-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) FAEPA National Institute for Translational Neuroscience Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Background: Slice cultures have been prepared from several organs. With respect to the brain, advantages of slice cultures over dissociated cell cultures include maintenance of the cytoarchitecture and neuronal connectivity. Slice cultures from adult human brain have been reported and constitute a promising method to study neurological diseases. Despite this potential, few studies have characterized in detail cell survival and function along time in short-term, free-floating cultures. New Method: We used tissue from adult human brain cortex from patients undergoing temporal lobectomy to prepare 200 pm-thick slices. Along the period in culture, we evaluated neuronal survival, histological modifications, and neurotransmitter release. The toxicity of Alzheimer's-associated A beta oligomers (A beta Os) to cultured slices was also analyzed. Results: Neurons in human brain slices remain viable and neurochemically active for at least four days in vitro, which allowed detection of binding of A beta Os. We further found that slices exposed to A beta Os presented elevated levels of hyperphosphorylated Tau, a hallmark of Alzheimer's disease. Comparison with Existing Method(s): Although slice cultures from adult human brain have been previously prepared, this is the first report to analyze cell viability and neuronal activity in short-term free-floating cultures as a function of days in vitro. Conclusions: Once surgical tissue is available, the current protocol is easy to perform and produces functional slices from adult human brain. These slice cultures may represent a preferred model for translational studies of neurodegenerative disorders when long term culturing in not required, as in investigations on A beta O neurotoxicity. Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto, SP, Brazil Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol & Forens Med, Ribeirao Preto, SP, Brazil Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Physiol, Ribeirao Preto, SP, Brazil Univ Fed Rio de Janeiro, Inst Med Biochem, Rio De Janeiro, RJ, Brazil Sao Paulo State Univ, Inst Biosci, Dept Anat, Sao Paulo, Brazil Univ Fed Rio de Janeiro, Inst Biomed Sci, Rio De Janeiro, RJ, Brazil Queens Univ, Ctr Neurosci Studies, Dept Biomed & Mol Sci, Kingston, ON, Canada Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Rio De Janeiro, RJ, Brazil Univ Sao Paulo, Ribeirao Preto Med Sch, Clin Hosp, Ribeirao Preto, SP, Brazil Northwestern Univ, Dept Neurobiol, Evanston, IL 60208 USA Univ Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, Rio De Janeiro, RJ, Brazil Barretos Canc Hosp, Barretos, SP, Brazil Sao Paulo State Univ, Inst Biosci, Dept Anat, Sao Paulo, Brazil