modeling-amyloid-42-toxicity-neurodegeneration-adult-zebrafish

Modeling Amyloid-&#946;42 Toxicity and Neurodegeneration in Adult Zebrafish Brain

Alzheimer's disease (AD) is a debilitating neurodegenerative disease in which accumulation of toxic amyloid-&#946;42 (A&#946;42) peptides leads to ...

TU Dresden

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and a worldwide health challenge. Different therapeutic approaches are being developed to reverse or slow the loss of affected neurons. Another plausible therapeutic way that may complement the studies is to increase the survival of existing neurons by mobilizing the existing neural stem/progenitor cells (NSPCs) - i.e. "induce their plasticity" - to regenerate lost neurons despite the existing pathology and unfavorable environment. However, there is controversy about how NSPCs are affected by the unfavorable toxic environment during AD. In this review, we will discuss the use of stem cells in neurodegenerative diseases and in particular how NSPCs affect the AD pathology and how neurodegeneration affects NSPCs. In the end of this review, we will discuss how zebrafish as a useful model organism with extensive regenerative ability in the brain might help to address the molecular programs needed for NSPCs to respond to neurodegeneration by enhanced neurogenesis.

Neural stem/progenitor cells in Alzheimer's disease.

Human brains are prone to neurodegeneration, given that endogenous neural stem/progenitor cells (NSPCs) fail to support neurogenesis. To investigate the molecular programs potentially mediating neurodegeneration-induced NSPC plasticity in regenerating organisms, we generated an Amyloid-β42 (Aβ42)-dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating Aβ42 derivatives. Aβ42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits. Aβ42 also induces NSPC proliferation and enhanced neurogenesis. Interleukin-4 (IL4) is activated primarily in neurons and microglia/macrophages in response to Aβ42 and is sufficient to increase NSPC proliferation and neurogenesis via STAT6 phosphorylation through the IL4 receptor in NSPCs. Our results reveal a crosstalk between neurons and immune cells mediated by IL4/STAT6 signaling, which induces NSPC plasticity in zebrafish brains.

IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain.

Microtubule-associated TAU protein is a pathological hallmark in Alzheimer's disease (AD), where hyperphosphorylation of TAU generates neurofibrillary tangles. To investigate the effects of TAU in a regenerative adult vertebrate brain system, we generated a cre/lox-based transgenic model of zebrafish that chronically expresses human TAU(P301L), which is a variant of human TAU protein that forms neurofibrillary tangles in mouse models and humans. Interestingly, we found that although chronic and abundant expression of TAU(P301L) starting from early embryonic development led to hyperphosphorylation, TAU(P301L) did not form oligomers and neurofibrillary tangles, and did not cause elevated apoptosis and microglial activation, which are classical symptoms of tauopathies in mammals. Additionally, TAU(P301L) neither increased neural stem cell proliferation nor activated the expression of regenerative factor Interleukin-4, indicating that TAU(P301L) toxicity is prevented in the adult zebrafish brain. By combining TAU(P301L) expression with our established Aβ42 toxicity model, we found that Aβ42 ceases to initiate neurofibrillary tangle formation by TAU(P301L), and TAU(P301L) does not exacerbate the toxicity of Aβ42. Therefore, our results propose a cellular mechanism that protects the adult zebrafish brain against tauopathies, and our model can be used to understand how TAU toxicity can be prevented in humans.

Article	Year
Neural stem/progenitor cells in Alzheimer's disease. The Yale journal of biology and medicine\| PubMed ID: 27505014	2016
IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain. Cell reports\| PubMed ID: 27760324	2016
Human TAU(P301L) overexpression results in TAU hyperphosphorylation without neurofibrillary tangles in adult zebrafish brain. Scientific reports\| PubMed ID: 29021554	2017

Violeta Mashkaryan

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