The neuroprotective N-terminal amyloid-β core hexapeptide reverses reactive gliosis and gliotoxicity in Alzheimer's disease pathology models

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by accumulation of extracellular amyloid beta (A beta) and intracellular neurofibrillary tangles, leading to chronic activation of astrocytes and microglia and persistent neuroinflammation. A beta-linked activation of microglia and astrocytes leads to increased intracellular calcium and production of proinflammatory cytokines, impacting the progression of neurodegeneration. An N-terminal A beta fragment (A beta(1-15)) and a shorter hexapeptide core sequence within the N-A beta fragment (N-A beta core: A beta(10-15)) have previously been shown to protect against A beta-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-A beta fragment and N-A beta core are protective against A beta-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-A beta core 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 A beta at concentrations mimicking the pathogenic concentrations (mu M) observed in AD in the absence or presence of the non-toxic N-terminal A beta 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 A beta fragments mitigated the phenotypic switch leading to astrogliosis and microgliosis induced by pathological concentrations of A beta in mixed glial cultures and organotypic brain slice cultures from the transgenic 5xFAD mouse model, while protecting against A beta-induced oxidative stress, mitochondrial dysfunction and apoptosis in isolated astrocytes and microglia. Moreover, the addition of the N-A beta core attenuated the expression and release of proinflammatory mediators in microglial cells activated by A beta and rescued microgliamediated loss of synaptic elements induced by pathological levels of A beta. Conclusions Together, these findings indicate the protective functions of the N-terminal A beta fragments extend to reactive gliosis and gliotoxicity induced by A beta, by preventing or reversing glial reactive states indicative of neuroinflammation and synaptic loss central to AD pathogenesis.

Automated summary

Alzheimer's disease is characterized by the accumulation of amyloid beta (Aβ) and neurofibrillary tangles, leading to chronic neuroinflammation. The N-terminal Aβ fragment and N-Aβ core have been shown to protect against neurodegeneration. This study provides evidence that these fragments can also alleviate persistent neuroinflammation in Alzheimer's disease.