Treating hippocampal neural stem cells with nano-pulsed laser therapy generates neurons with decreased sensitivity to toxic Aβ oligomers.

Synaptic dysfunction driven by toxic amyloid oligomers (Abo and Tauo) is an early event leading to cognitive decline in Alzheimer's disease (AD). We have shown that transcranial treatment of adult wt mice with near-infrared light decreases synaptic vulnerability to Aβo. We have also shown that preserved neurogenesis correlates with synaptic resilience and preserved cognitive function in non-demented individuals with AD neuropathology. Here we sought to determine whether treating hippocampal neural stem cells (NSCs), the primary source of neurogenesis in the adult brain, with Nano-Pulsed Laser Therapy (NPLT), combining near-infrared light irradiation (808nm) with ultrasonic optoacoustic waves, could lead to the generation of neurons with decreased synaptic vulnerability to Aβo toxicity. Adult rat hippocampal NSCs were treated for five minutes with NPLT (10ms pulse duration, 20Hz pulse frequency, 4.3mJ total energy) or sham treatment and allowed to differentiate into mature neurons (MN) for five days. For analysis of Abo binding, MNs were exposed to 2.5µM Fluor-647-labeled Aβo for 30 minutes at 37⁰C and immunostained for βIII-tubulin. The number of Aβo puncta on neurites was quantified using ImageJ. For analysis of mitochondrial function, Aβo-treated MNs were incubated with the mitochondrial membrane potential-dependent dye, MitoTracker Deep Red (MTDR) and potential-independent MitoTracker Green (MTG). Flow cytometric analyses of MTDR (healthy mitochondria) and MTG (total mitochondria) was conducted at 30 minutes post-Aβo treatment. MNs generated from NPLT-treated NSCs showed significantly fewer Aβo puncta per neurite compared to MNs from sham-treated NSCs (p=0.0049), and lower percentage of total neurites with bound Aβo (p<0.0001) (Figure 1). We also found that Aβo treatment induced a significant reduction in both total mitochondria and mitochondrial membrane potential in MNs from sham-treated NSCs but not in MNs from NPLT-treated NSCs (Figure 2). Here we show that NSCs treated with NPLT generate MNs resistant to Aβo binding and to Ab-induced mitochondrial dysfunction. These data suggest that NPLT, which is currently approved for use in humans for unrelated clinical applications, could be a valuable therapeutic tool for inducing cognitive resilience to AD neuropathology. © 2021 the Alzheimer's Association.

Citation

Kevin J Johnson, Auston Cody Grant, Kathia Johnson, Rinat Esenaliev, Giulio Taglialatela, Maria-Adelaide Micci. Treating hippocampal neural stem cells with nano-pulsed laser therapy generates neurons with decreased sensitivity to toxic Aβ oligomers. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021 Dec;17 Suppl 3:e057482

PMID: 35109366

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