| First Author | Lantz MJ | Year | 2023 |
| Journal | J Neuroinflammation | Volume | 20 |
| Issue | 1 | Pages | 129 |
| PubMed ID | 37245024 | Mgi Jnum | J:348190 |
| Mgi Id | MGI:7487417 | Doi | 10.1186/s12974-023-02807-9 |
| Citation | Lantz MJ, et al. (2023) The neuroprotective N-terminal amyloid-beta core hexapeptide reverses reactive gliosis and gliotoxicity in Alzheimer's disease pathology models. J Neuroinflammation 20(1):129 |
| abstractText | BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by accumulation of extracellular amyloid beta (Abeta) and intracellular neurofibrillary tangles, leading to chronic activation of astrocytes and microglia and persistent neuroinflammation. Abeta-linked activation of microglia and astrocytes leads to increased intracellular calcium and production of proinflammatory cytokines, impacting the progression of neurodegeneration. An N-terminal Abeta fragment (Abeta(1-15)) and a shorter hexapeptide core sequence within the N-Abeta fragment (N-Abetacore: Abeta(10-15)) have previously been shown to protect against Abeta-induced mitochondrial dysfunction, oxidative stress and apoptosis in neurons and rescue synaptic and spatial memory deficits in an APP/PSEN1 mouse model. Here, we hypothesized that the N-Abeta fragment and N-Abetacore are protective against Abeta-induced gliotoxicity, promoting a neuroprotective environment and potentially alleviating the characteristically persistent neuroinflammation present in AD. METHODS: We treated ex vivo organotypic brain slice cultures from an aged familial AD mouse model, 5xFAD, with the N-Abetacore and used immunocytochemistry to assess the impact on astrogliosis and microgliosis and alterations in synaptophysin-positive puncta engulfed by microglia. Isolated neuron/glia cultures, mixed glial cultures or a microglial cell line were treated with oligomeric human Abeta at concentrations mimicking the pathogenic concentrations (muM) observed in AD in the absence or presence of the non-toxic N-terminal Abeta fragments. Resultant changes in synaptic density, gliosis, oxidative stress, mitochondrial dysfunction, apoptosis, and the expression and release of proinflammatory markers were then determined. RESULTS: We demonstrate that the N-terminal Abeta fragments mitigated the phenotypic switch leading to astrogliosis and microgliosis induced by pathological concentrations of Abeta in mixed glial cultures and organotypic brain slice cultures from the transgenic 5xFAD mouse model, while protecting against Abeta-induced oxidative stress, mitochondrial dysfunction and apoptosis in isolated astrocytes and microglia. Moreover, the addition of the N-Abetacore attenuated the expression and release of proinflammatory mediators in microglial cells activated by Abeta and rescued microglia-mediated loss of synaptic elements induced by pathological levels of Abeta. CONCLUSIONS: Together, these findings indicate the protective functions of the N-terminal Abeta fragments extend to reactive gliosis and gliotoxicity induced by Abeta, by preventing or reversing glial reactive states indicative of neuroinflammation and synaptic loss central to AD pathogenesis. |
