The effects of aging on Amyloid-β42-induced neurodegeneration and regeneration in adult zebrafish brain

Abstract

Alzheimer disease is the most prevalent neurodegenerative disease and is associated with aggregation of Amyloid-β42 peptides. In mammals, Amyloid-β42 causes impaired neural stem/progenitor cell (NSPC) proliferation and neurogenesis, which exacerbate with aging. The molecular programs necessary to enhance NSPC proliferation and neurogenesis in our brains to mount successful regeneration are largely unknown. Therefore, to identify the molecular basis of effective brain regeneration, we previously established an Amyloid-β42 model in adult zebrafish that displayed Alzheimer-like phenotypes reminiscent of humans. Interestingly, zebrafish exhibited enhanced NSPC proliferation and neurogenesis after microinjection of Amyloid-β42 peptide. Here, we compare old and young fish to address the effects of aging on regenerative ability after Amyloid-β42 deposition. We found that aging does not affect the rate of NSPC proliferation but reduces the neurogenic response and microglia/macrophage activation after microinjection of Amyloid-β42 in zebrafish, suggesting an important link between aging, neuroinflammation, regenerative neurogenesis and neural stem cell plasticity.

Single cell analyses of the effects of Amyloid-beta42 and Interleukin-4 on neural stem/progenitor cell plasticity in adult zebrafish brain

“…Interestingly, a master regulator of neural stem cell plasticity sox2 is upregulated in all RGC clusters as well as in NBs and in no other cell type after Aβ42 treatment (Figure 4I). This indicates an interesting finding that Aβ42 enhances NSPC plasticity in all glial cells and neuroblasts and provides a molecular explanation on our previous findings that NSPC proliferation increases after Aβ42 (Bhattarai et al, 2016a; Bhattarai et al, 2017a; Bhattarai et al, 2017b). Therefore, we propose that the regenerative ability of adult zebrafish brain after Aβ42 toxicity might rely on the ability of the NSPCs to upregulate sox2 expression.…”

“…We previously showed that Aβ42 treatment causes phenotypes reminiscent of human AD conditions, namely, cell death, synaptic degeneration, inflammation and cognitive deficits (Bhattarai et al, 2017a; Bhattarai et al, 2016b; Bhattarai et al, 2017b). However, in contrast to mammals, zebrafish NSPCs increased their proliferation and neurogenic output indicating that adult zebrafish brain responds to Aβ42 toxicity by enhancing NSPC plasticity and neuroregeneration (Bhattarai et al, 2016b; Bhattarai et al, 2017b). We also identified Interleukin-4 (IL4) as a crosstalk mechanism that activates the NSPCs and kick-starts the regeneration response (Bhattarai et al, 2016b).…”

“…Central nervous system regeneration is catching particular attention because of robust neural regeneration ability in zebrafish and clinical ramifications it might bring, which could not be possible to elucidate with mammalian models. For instance, we have recently generated an Amyloid toxicity model in adult zebrafish brain and identified that zebrafish can effectively enhance its neural stem cell proliferation and neurogenesis with key activity of Interleukin-4 (IL4) that mediates the crosstalk between disease pathology in neurons and initiation of regenerative output in stem cells (Bhattarai et al, 2017a; Bhattarai et al, 2016b; Bhattarai et al, 2017b; Kizil, 2018). We also found that IL4 can directly affect the human neural stem cells in a similar fashion to induce the proliferative and neurogenic ability (Papadimitriou et al, 2018).…”

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

“…Since Aβ42/IL4 enhances neural stem cell (NSC) proliferation in adult zebrafish brain (Bhattarai et al, 2017a;Bhattarai et al, 2016;Bhattarai et al, 2017b;Kizil, 2018;Kizil and Bhattarai, 2018b) and they downregulate 5-HT ( Figure 1E,F), we hypothesized that 5-HT could be negatively affecting NSC plasticity. To test this, we injected 5-HT into adult zebrafish brain and analyzed the proliferation of NSCs (S100b/PCNA double positive cells) (Figure 2A-C).…”

“…Amyloid-β42 (Aβ42) synthesis was performed as described . Cerebroventricular microinjection in adult zebrafish brain were performed as previously described (Bhattarai et al, 2017a;Bhattarai et al, 2016;Bhattarai et al, 2017b). PBS (1μl), Aβ42 (1 μl, 20 μM), IL4 (1 μl, 10 μg/ml), BDNF (1 μl, 100ng/ml), 5-HT (1 μl, 100 μM), ngfra morpholino (1μl, 10uM) were injected.…”