Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer's disease mouse model promotes synaptic resilience.

Current approaches in treatment of Alzheimer's disease (AD) is focused on early stages of cognitive decline. Identifying therapeutic targets that promote synaptic resilience during early stages may prevent progressive memory deficits by preserving memory mechanisms. We recently reported that the inducible isoform of phospholipase D (PLD1) was significantly increased in synaptosomes from post-mortem AD brains compared to age-matched controls. Using mouse models, we reported that the aberrantly elevated neuronal PLD1 is key for oligomeric amyloid driven synaptic dysfunction and underlying memory deficits. Here, we demonstrate that chronic inhibition using a well-tolerated PLD1 specific small molecule inhibitor is sufficient to prevent the progression of synaptic dysfunction during early stages in the 3xTg-AD mouse model. Firstly, we report prevention of cognitive decline in the inhibitor-treated group using novel object recognition (NOR) and fear conditioning (FC). Secondly, we provide electrophysiological assessment of better synaptic function in the inhibitor-treated group. Lastly, using Golgi staining, we report that preservation of dendritic spine integrity as one of the mechanisms underlying the action of the small molecule inhibitor. Collectively, these studies provide evidence for inhibition of PLD1 as a potential therapeutic strategy in preventing progression of cognitive decline associated with AD and related dementia.

Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides.

The brains of Alzheimer's disease (AD) patients display cerebrovascular and parenchymal deposits of beta-amyloid (A beta) peptides, which are derived by proteolytic processing by the beta-site APP-cleaving enzyme 1 (BACE1) of the amyloid precursor protein (APP). The rat BACE1 promoter has a nuclear factor-kappaB (NF-kappaB) binding site. Deletion studies with a BACE1 promoter/luciferase reporter suggest that the NF-kappaB binding DNA consensus sequence plays a suppressor role, when occupied by NF-kappaB, in the regulation of neuronal brain BACE1 expression. Here we characterize a signal transduction pathway that may be responsible for the increases in A beta associated with AD. We propose that the transcription factor NF-kappaB acts as a repressor in neurons but as an activator of BACE1 transcription in activated astrocytes present in the CNS under chronic stress, a feature present in the AD brain. The activated astrocytic stimulation of BACE1 may in part account for increased BACE1 transcription and subsequent processing of Ab eta in a cell-specific manner in the aged and AD brain. As measured by reporter gene promoter constructs and endogenous BACE1 protein expression, a functional NF-kappaB site was stimulatory in activated astrocytes and A beta-exposed neuronal cells and repressive in neuronal and nonactivated astrocytic cells. Given the evidence for increased levels of activated astrocytes in the aged brain, the age- and AD-associated increases in NF-kappaB in brain may be significant contributors to increases in A beta, acting as a positive feedback loop of chronic inflammation, astrocyte activation, increased p65/p50 activation of BACE1 transcription, and further inflammation.