The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD-linked amyloid-ß oligomers (AßOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AßOs into the lateral cerebral ventricle of non-human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD-related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP-1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Alzheimer's disease-like pathology induced by amyloid-ß oligomers in nonhuman primates.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a major medical problem. Here, we have investigated the impact of amyloid-ß (Aß) oligomers, AD-related neurotoxins, in the brains of rats and adult nonhuman primates (cynomolgus macaques). Soluble Aß oligomers are known to accumulate in the brains of AD patients and correlate with disease-associated cognitive dysfunction. When injected into the lateral ventricle of rats and macaques, Aß oligomers diffused into the brain and accumulated in several regions associated with memory and cognitive functions. Cardinal features of AD pathology, including synapse loss, tau hyperphosphorylation, astrocyte and microglial activation, were observed in regions of the macaque brain where Aß oligomers were abundantly detected. Most importantly, oligomer injections induced AD-type neurofibrillary tangle formation in the macaque brain. These outcomes were specifically associated with Aß oligomers, as fibrillar amyloid deposits were not detected in oligomer-injected brains. Human and macaque brains share significant similarities in terms of overall architecture and functional networks. Thus, generation of a macaque model of AD that links Aß oligomers to tau and synaptic pathology has the potential to greatly advance our understanding of mechanisms centrally implicated in AD pathogenesis. Furthermore, development of disease-modifying therapeutics for AD has been hampered by the difficulty in translating therapies that work in rodents to humans. This new approach may be a highly relevant nonhuman primate model for testing therapeutic interventions for AD.

Comparison between suture and fibrin glue on repair by direct coaptation or tubulization of injured mouse sciatic nerve.

PURPOSE: The aim of this study was to evaluate and compare the effectiveness of classical suture and sutureless repair with fibrin glue, by using or not a resorbable collagen tube, after sciatic nerve transection. MATERIAL AND METHODS: Twenty-five mice were used in this study, divided in five groups. They were submitted to sciatic nerve transection and immediate repair of the nerve stumps by either direct suture or fibrin glue adhesion or by the tubulization technique in which the nerves stumps were sutured or glued to a collagen tube (experimental groups). A control group was designed as the best regeneration condition, by using a crush lesion (control group). After eight weeks, the regenerated nerves were processed for light and electron microscopy. Motor function analysis was performed using the sciatic functional index. RESULTS: Quantitative analysis of regenerated nerves between experimental groups showed that those repaired by direct contact of the stumps with fibrin glue showed significant increase in the myelin and fiber areas. The tubulization groups, repaired by suture or fibrin glue, provided similar results. G-ratio analysis revealed that the regenerating axons of all experimental groups presented values equivalent to control (crushing group). CONCLUSIONS: These results suggest that the use of fibrin glue in nerve repair by either direct coaptation or tubulization is an alternative to conventional suture repair, particularly in case of small-size-nerve reconstruction.

A novel approach to increase glial cell populations in brain microphysiological systems.

Brain microphysiological systems (bMPS), which recapitulate human brain cellular architecture and functionality more closely than traditional monolayer cultures, have become a practical, non-invasive, and increasingly relevant platform for the study of neurological function in health and disease. These models include 3D spheroids and organoids as well as organ-on-chip models. Currently, however, existing 3D brain models vary in reflecting the relative populations of the different cell types present in the human brain. Most of the models consist mainly of neurons, while glial cells represent a smaller portion of the cell populations. Here, by means of a chemically defined glial-enriched medium (GEM), we present an improved method to expand the population of astrocytes and oligodendrocytes without compromising neuronal differentiation in bMPS. An important finding is that astrocytes not only increased in number but also changed in morphology when cultured in GEM, more closely recapitulating primary culture astrocytes. We demonstrate oligodendrocyte and astrocyte enrichment in GEM bMPS using a variety of complementary methods. We found that GEM bMPS are electro-chemically active and showed different patterns of Ca +2 staining and flux. Synaptic vesicles and terminals observed by electron microscopy were also present. No significant changes in neuronal differentiation were observed by gene expression, however, GEM enhanced neurite outgrowth and cell migration, and differentially modulated neuronal maturation in two different iPSC lines. Our results have the potential to significantly improve in vivo-like functionality of bMPS for the study of neurological diseases and drug discovery, contributing to the unmet need for safe human models.

A Novel Approach to Increase Glial Cell Populations in Brain Microphysiological Systems.

Brain microphysiological systems (bMPS) recapitulate human brain cellular architecture and functionality more closely than traditional monolayer cultures and have become increasingly relevant for the study of neurological function in health and disease. Existing 3D brain models vary in reflecting the relative populations of different cell types present in the human brain. Most models consist mainly of neurons, while glial cells represent a smaller portion of the cell populations. Here, by means of a chemically defined glial-enriched medium (GEM), an improved method to expand the population of astrocytes and oligodendrocytes without compromising neuronal differentiation in bMPS, is presented. An important finding is that astrocytes also change in morphology when cultured in GEM, more closely recapitulating primary culture astrocytes. GEM bMPS are electro-chemically active and show different patterns of calcium staining and flux. Synaptic vesicles and terminals observed by electron microscopy are also present. No significant changes in neuronal differentiation are observed by gene expression, however, GEM enhanced neurite outgrowth and cell migration, and differentially modulated neuronal maturation in two different cell lines. These results have the potential to significantly improve functionality of bMPS for the study of neurological diseases and drug discovery, contributing to the unmet need for safe human models.

Grafts of human adipose-derived stem cells into a biodegradable poly (acid lactic) conduit enhances sciatic nerve regeneration.

Despite the regenerative potential of the Peripheral Nervous System (PNS), injuries with loss of a nerve segment make the functional recovery a challenge. This work aimed to investigate the effects of the association of biodegradable conduits of poly (lactic acid) (PLA) with human adipose-derived stem cells (hADSCs) on the regeneration of the sciatic nerve. C57BL / 6 male mice were submitted to sciatic nerve transection followed by tubulization with PLA conduit. Animals were allocated in two groups: the first received an injection of DMEM inside the conduit (DMEM) and the second received hADSCs inside it (hADSC). Sensory and motor functions were assessed by the pinprick test and electroneuromiography, respectively. To assess neuronal survival the retrograde tracer fluorogold was injected into the sciatic nerve distally to the lesion site. One week after that, animals were sacrificed, tissues harvested and processed for morphological evaluation. After eight weeks, all animals showed sensory recovery in the pinprick test and there was no significant difference between the two groups. The amplitude of the compound muscle action potential was higher in the hADSCs group. The number of myelinated nerve fibers, muscle cells and motor plates was higher in the hADSC group. There was also greater survival of sensory and motor neurons in the hADSC animals. These results suggest that the association of PLA conduit and cell therapy with hADSCs leads to a better functional and morphological recovery after sciatic nerve transection.