Abstract
Background: Recent research has identified the nucleotide polymorphisms of KIdney and BRAin expressed protein (KIBRA) to be associated with cognitive performance, suggesting its vital role in Alzheimer’s disease (AD); however, the underlying molecular mechanism of KIBRA in AD remains obscure.Methods: The AD animal model (APP/PS1 transgenic mice) and KIBRA knockout (KIBRA KO) mice were used to investigate pathophysiological changes of KIBRA in vivo. Mouse hippocampal cell line (HT22) was used to explore its molecular mechanism through KIBRA CRISPR/Cas9-sgRNA system and KIBRA overexpression lentivirus in vitro.Results: Aged APP/PS1 mice displayed increased neuronal apoptosis in the hippocampus, as did KIBRA KO mice. KIBRA deficiency was closely related to neuronal loss in the brain. In addition, knockdown of KIBRA in neuronal cell lines suppressed its growth and elevated apoptosis-associated protein levels under the stress of Aβ1–42 oligomers. On the contrary, overexpression of KIBRA significantly promoted cell proliferation and reduced its apoptosis. Moreover, through screening several survival-related signaling pathways, we found that KIBRA inhibited apoptosis by activating the Akt pathway other than ERK or PKC pathways, which was further confirmed by Akt-specific inhibitor MK2206.Conclusion: Our data indicate that KIBRA may function as a neuroprotective gene in promoting neuron survival and inhibiting Aβ-induced neuronal apoptosis.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by progressive cognitive deterioration, with the number of people affected by AD being projected to double over the 35 years (Prince et al, 2015)
Overexpression of KIdney and BRAin expressed protein (KIBRA) in neuronal cell lines significantly promoted its proliferation and inhibited Aβ-induced apoptosis through activation of Akt pathway but not ERK or PKC pathways, which was further confirmed by Akt-specific inhibitor MK2206
To investigate whether KIBRA exerted a protective role against neuronal apoptosis, we evaluated used by immunofluorescent staining of Tuj1 and TUNEL in APP/PS1 mice and KIBRA KO mice
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by progressive cognitive deterioration, with the number of people affected by AD being projected to double over the 35 years (Prince et al, 2015). The extracellular accumulation of amyloid-β (Aβ) plaques and the intracellular formation of neurofibrillary tangles (NFTs) in the brain are known to play critical roles in the pathogenesis of AD (Jack et al, 2010). According to the ‘‘Amyloid Cascade Hypothesis’’ (Hardy and Higgins, 1992; Hardy and Selkoe, 2002), KIBRA Protects Neuron Against Amyloid-β. Aβ deposition is the initial pathological trigger in the disease, which subsequently leads to the formation of NFTs, neuronal cell death, and the expression of dementia (Reitz, 2012). Recent research has identified the nucleotide polymorphisms of KIdney and BRAin expressed protein (KIBRA) to be associated with cognitive performance, suggesting its vital role in Alzheimer’s disease (AD); the underlying molecular mechanism of KIBRA in AD remains obscure
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