Alzheimer's disease (AD) is characterized phenotypically by memory impairment, histologically by accumulation of pTau and β-amyloid peptide and morphologically by a loss of nerve terminals in cortical and hippocampal regions. As glutamate is the principle excitatory neurotransmitter of the central nervous system (CNS), the glutamatergic system may play an important role in AD. To date, not many studies have addressed the deleterious effects of Aβ on glutamatergic terminals; therefore the aim of this study was to investigate how Aβ affects glutamatergic terminals and to assess the extent to which alterations in the glutamatergic neurotransmission could impact susceptibility to the illness. The present study shows that Aβ caused a loss of glutamatergic terminals, measured by VGLUT1 protein levels, in Tg2576 primary cell cultures, Tg2576 mice and AD patient brains, and also when Aβ was added exogenously to hippocampal cell cultures. Interestingly, no correlation was found between cognition and decreased VGLUT1 levels. Moreover, when Aβ1-42 was intracerebroventricularlly administered into VGLUT1+/- mice, altered synaptic plasticity and increased neuroinflammation was observed in the hippocampus of those animals. In conclusion, the present study not only revealed susceptibility of glutamatergic nerve terminals to Aβ induced toxicity but also underlined the importance of VGLUT1 in the progression of AD, as the decrease of this protein levels could increase the susceptibility to subsequent deleterious inputs by exacerbating Aβ induced neuroinflammation and synaptic plasticity disruption. © 2016 Wiley Periodicals, Inc.

The concept of central insulin resistance and dysfunctional insulin signalling in sporadic Alzheimer's disease (AD) is now widely accepted and diabetes is recognized as one of the main risk factors for developing AD. Moreover, some lines of evidence indicated that VGlut1 is impaired in frontal regions of AD patients and this impairment is correlated with the progression of cognitive decline in AD. The present work hypothesizes that ketosis associated to insulin resistance could interfere with the normal activity of VGlut1 and its role in the release of glutamate in the hippocampus, which might ultimately lead to cognitive deficits. High fat diet (HFD) rats showed memory impairments and both peripheral (as shown by increased fasting plasma insulin levels and HOMA index) and hippocampal (as shown by decreased activation of insulin receptor, IRS-1 and pAkt) insulin pathway alterations, accompanied by increased ketone bodies production. All these effects were counteracted by α-lipoic acid (LA) administration. VGlut1 levels were significantly decreased in the hippocampus of HFD rats, and this decrease was reversed by LA. Altogether, the present results suggest that HFD induced alterations in central insulin signalling could switch metabolism to produce ketone bodies, which in turn, in the hippocampus, might lead to a decreased expression of VGlut1, and therefore to a decreased release of glutamate and hence, to the glutamatergic deficit described in AD. The ability of LA treatment to prevent the alterations in insulin signalling in this model of HFD might represent a possible new therapeutic target for the treatment of AD.

The crosstalk between cancer cells and tumor associated macrophages (TAMs) within the tumor environment modulates tumor progression at all stages of cancer disease. TAMs are predominantly M2-like polarized macrophages with tumor-promoting activities. Nonetheless, they can be repolarized to tumoricidal M1-like macrophages through macrophage colony stimulating factor 1 receptor inhibition (CSF1Ri). CSF1Ri is being explored as multifaced therapeutic approach to suppress TAMs tumorpromoting functions and reduce cancer cell aggressiveness and viability. However, treatment with CSF1Ri results in significant TAMs death, thereby extinguishing the possibility of generating tumoricidal M1-like macrophages. Immunotherapy has improved overall patient's survival in some cancer types, but also caused frequent off-target toxicity. Approaches to balance efficacy vs toxicity are needed. Herein, a CSF1Ri loaded polymersomes (PM) based delivery platform is developed to promote M2-like macrophage repolarization. When testing in vitro on primary human monocyte-derived macrophages (MDMs), CSF1Ri loaded PM are preferentially taken up by M2-like macrophages and enhance M2 to M1-like macrophage repolarization while minimizing cytotoxicity in comparison to the free drug. When testing in a MDMs-MDA-MB-231 breast cancer cell co-culture model, CSF1Ri loaded PM further retain their M2 to M1-like macrophages polarization capacity. This CSF1Ri loaded PMbased platform system represents a promising tool for macrophage-based immunotherapy approaches.Received: ((will be filled in by the editorial staff))Revised: ((will be filled in by the editorial staff))

The complex interaction between tumor-associated macrophages (TAMs) and tumor cells through soluble factors provides essential cues for breast cancer progression. TAMs-targeted therapies have shown promising clinical therapeutical potential against cancer progression. The molecular mechanisms underlying the response to TAMs-targeted therapies depends on complex dynamics of immune cross-talk and its understanding is still incomplete. In vitro models are helpful to decipher complex responses to combined immunotherapies. In this study, we established and characterized a 3D human macrophage-ER+ PR+ HER2+ breast cancer model, referred to as macrophage-tumor spheroid (MTS). Macrophages integrated within the MTS had a mixed M2/M1 phenotype, abrogated the anti-proliferative effect of trastuzumab on tumor cells, and responded to IFNγ with increased M1-like polarization. The targeted treatment of MTS with a combined CSF1R kinase inhibitor and an activating anti-CD40 antibody increased M2 over M1 phenotype (CD163+/CD86+ and CD206+/CD86+ ratio) in time, abrogated G2/M cell cycle phase transition of cancer cells, promoted the secretion of TNF-α and reduced cancer cell viability. In comparison, combined treatment in a 2D macrophage-cancer cell co-culture model reduced M2 over M1 phenotype and decreased cancer cell viability. Our work shows that this MTS model is responsive to TAMs-targeted therapies, and may be used to study the response of ER+ PR+ HER2+ breast cancer lines to novel TAM-targeting therapies.

In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer's disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD.