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TREATING HIPPOCAMPAL NEURAL STEM CELLS WITH NANO-PULSED LASER THERAPY GENERATES NEURONS RESILIENT AGAINST Aβ OLIGOMER TOXICITY

ABSTRACT: Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and despite the passage of over a century since its discovery, we have yet to discover a cure. Hippocampal synaptic dysfunction driven by toxic amyloid-β oligomers (AβO) is an early event in the progression of neurodegeneration and cognitive decline in AD. Non-invasive therapies such as photobiomodulation (PBM) are receiving increased attention in AD research due to the accessibility and relative safety compared to novel drug trials, and have been shown to induce synaptic resilience in animal models of AD. Nano-pulsed laser therapy (NPLT) is a type of PBM therapy using pulsed 808nm near-infrared laser light and optoacoustically generated ultrasound waves to stimulate deeper brain structures than would be accessible by traditional PBM therapy. Here we use NPLT to stimulate adult hippocampal neural stem cells (NSC) and differentiate them in vitro to assess resilience of the mature neurons against AβO toxicity. We found that neurons differentiated from NPLT-treated NSC are resilient against AβO binding and mitochondrial toxicity, and show increased expression of genes associated with autophagy and proteostasis.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE308539 | GEO | 2026/04/15

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is a major neurodegenerative disease characterized by extracellular amyloid β (Aβ) plaques and intracellular hyperphosphorylated tau (P-tau). Increasing evidence indicates that extracellular vesicles (EVs) play an important role in AD pathogenesis. We previously reported that the choroid plexus epithelial (CPE) cells, present at the interface between blood and cerebrospinal fluid (CSF), show increased secretion of EVs into the CSF in response to peripheral inflammation. Here, we studied the importance of CP-derived EVs in AD pathogenesis. We observed increased EV levels in the CSF of 7 weeks old transgenic APP/PS1 mice, correlating with higher Aβ CSF levels at this age, while levels normalized with age. To study whether the elevated Aβ CSF levels might be responsible for this increase, mice were intracerebroventricularly (icv) injected with Aβ oligomers (AβO) which revealed a significant increase in the amount of CD9 and CD81 positive EVs in the CSF. The importance of the CPE cells as EV source was shown by in vitro analysis of AβO stimulated primary CPE cells and in vivo analysis of the CP by transmission electron microscopy (TEM). Evaluation of EV marker immunostaining, both from AβO icv injected mice and APP/PS1 mice, confirmed the upregulation of EV biogenesis in the CP. Interestingly, AβO-induced, CP-derived EVs induced pro-inflammatory effects in mixed cortical cultures (MCC) whereas proteome analysis revealed the presence of complement protein C3, amongst other inflammatory proteins. Additionally, we could show for the first time that AβO induce an upregulation of C3 in CPE cells. These data highlight the CP and CP-derived, C3-containing EVs as novel players in the emerging importance of the complement pathway in the pathogenesis of AD. Strikingly, inhibition of EV production using GW4869 resulted in protection against the AβO-induced cognitive decline. In conclusion, our results show that intraventricular AβO induce both C3 activation and EV secretion by the CP and that these EVs contain pro-inflammatory molecules, including C3, which play a role in neuroinflammation and loss of cognition. This suggests that inhibition of EV production by the CP might be an interesting therapeutic approach to be explored in the prevention or treatment of AD.

Project description:Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nucleus transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid load. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GRIA3, KCNMA1, and STXBP1. This putative cell type has been implicated in resilience in previous studies on bulk RNA-seq tissue, but our single-nucleus and cross-species approach identifies particular resilience-associated gene signatures in these cells. These novel resilience candidate genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Based on these gene signatures, we identified several potential mechanisms of resilience, including regulation of synaptic plasticity, axonal and dendritic development, and neurite vesicle transport along microtubules that are potentially targetable by available therapeutics. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

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TREATING HIPPOCAMPAL NEURAL STEM CELLS WITH NANO-PULSED LASER THERAPY GENERATES NEURONS RESILIENT AGAINST Aβ OLIGOMER TOXICITY

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