Abstract
Glial-neuronal cross-talk has a critical role in the development of neurodegenerative conditions, including Alzheimer’s Disease, where it affects neuronal responses to β-amyloid peptide (Aβ)-induced toxicity. We set out to identify factors regulating synaptic responses to Aβ, dissecting the specific role of glial signaling. A low concentration of aggregated Aβ42 induced selective up-regulation of mature brain-derived neurotrophic factor (BDNF) expression and release in rat organotypic hippocampal cultures as well as in cortical pure microglia. Conditioned media from resting (CMC) or Aβ42-treated (CMA) microglia were tested for their effects on synaptophysin expression in SH-SY5Y neuronal-like cells during challenge with Aβ42. Both CMC and CMA prevented Aβ-induced synaptophysin loss. In the presence of Aβ + CMA, synaptophysin was over-expressed, although it appeared partly clumped in cell bodies. Synaptophysin over-expression was not directly dependent on BDNF signaling on neuronal-like cells, but relied on autocrine BDNF action on microglia. FM1-43 labeling experiments revealed compromised synaptic vesicle recycling in Aβ42-treated neuronal-like cells, rescued by microglial conditioned medium. In these conditions, significant and prolonged neuroprotection was observed. Our results point to microglia as a target for early intervention, given its positive role in supporting neuronal compensatory responses to Aβ synaptotoxicity, which potentially lead to their extended survival.
Highlights
Alzheimer’s Disease (AD) is a progressive neurodegenerative condition affecting millions worldwide, an incidence destined to increase along with population ageing[1,2]
Among the many effectors released by glial cells is brain-derived neurotrophic factor (BDNF), a neurotrophin characterized in AD by a biphasic pattern of expression with a significant rise in patients showing mild cognitive impairment (MCI), followed by a substantial drop in patients at more advanced stages of the disease, when neuritic degeneration and reduced spine density occur[13]
Aβ is a key molecular factor in the etiology of AD, primarily targeting synaptic function[19,20,21], in a process that is rather slow over the years before massive synaptic loss and neuronal degeneration occur[22,23,24]
Summary
Alzheimer’s Disease (AD) is a progressive neurodegenerative condition affecting millions worldwide, an incidence destined to increase along with population ageing[1,2]. Among the many effectors released by glial cells is brain-derived neurotrophic factor (BDNF), a neurotrophin characterized in AD by a biphasic pattern of expression with a significant rise in patients showing mild cognitive impairment (MCI), followed by a substantial drop in patients at more advanced stages of the disease, when neuritic degeneration and reduced spine density occur[13]. We explored the role of BDNF of glial origin, together with pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), as possible mediators of glia-neuron crosstalk in this context. To this end, we used organotypic hippocampal slices and individually cultured neuronal-like cells, astrocytes and microglia
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