Alzheimer’s disease (AD) is the most common type of dementia that occurs in the elderly. Amyloid hypothesis is one of the most studied pathological mechanisms, and β-amyloid (Aβ) is the drug target for most clinical trials. Mitochondrial dysfunction induced by the Aβ-precursor protein (APP)/Aβ has been suggested to play a key role in the development of AD. Here, we explored the effects of myricetin, a polyphenol compound abundant in fruits and vegetables, on mitochondrial damages in N2a-SW cells. After the treatment of myricetin, mitochondrial depolarization was improved by increasing the mitochondrial membrane potential. Mitochondrial biogenesis as well as mitochondrial genome integrity was enhanced via increased levels of PGC-1α, Nrf1, TFAM, and the copy number of mtDNA. Mitochondrial functions were restored as represented by the increased levels of proteins involved in the electron transport chain and the adenosine 5′-triphosphate (ATP) content and the decreased concentration of ROS. Mitochondrial dynamics and mitophagy were ameliorated through the regulation of proteins involved in fusion (OPA1 and Mfn2), fission (Drp1 and Fis1), and mitophagy (PINK1 and Parkin). Thus, it is summarized that myricetin could recover the mitochondrial impairments in N2a-SW cells, exhibiting the potential to promote neuroprotection for APP/Aβ-related diseases, including AD.

Class IIa histone deacetylases (HDAC) have been shown to drive innate immune cell-mediated inflammation in the peripheral system, but their roles in cerebral inflammatory responses remain largely unknown. Here, we elucidate that HDAC7 is selectively elevated in lipopolysaccharide (LPS)-challenged astrocytes both in vivo and in vitro. We identify that HDAC7 binds to the inhibitory kappa B kinase (IKK) to promote IKKα and IKKβ deacetylation and subsequent activation, leading to the activation of nuclear factor κB (NF-κB). Astrocyte-specific overexpression of HDAC7 results in NF-κB activation, pro-inflammatory gene upregulation and anxiety-like behaviors in mice, while downregulating HDAC7 reserves LPS-induced NF-κB activation and inflammatory responses. Furthermore, pharmacological inhibition of HDAC7 by a class IIa HDAC inhibitor attenuates LPS-induced NF-κB activation, inflammatory responses and anxiety-like behaviors both in vivo and in vitro. Together, our data reveal a novel mechanism of HDAC7 in astrocyte-mediated inflammation and suggest that targeting HDAC7 could be a potential therapeutic strategy for the treatment of anxiety and other inflammation-related diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-022-02965-6.

Intracellular tau accumulation is a hallmark pathology of Alzheimer’s disease (AD) and other tauopathies. Tau protein, in the hyperphosphorylated form, is the component of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) in AD. Blocking tau aggregation and/or phosphorylation is currently a promising strategy for AD treatment. Here, we elucidate that quercetagitrin, a natural compound derived from African marigold (Tagetes erecta), could inhibit tau aggregation and reduce tau phosphorylation at multiple disease-related sites in vitro. Moreover, the in vivo effect of quercetagitrin was assessed in P301S-tau transgenic via oral administration. The compound treatment restored the cognitive deficits and neuron loss in the mice. The formation of NFTs and tau phosphorylations in the hippocampus and cortex of the mice was also prevented by the compound. Moreover, quercetagitrin feeding displayed neuroinflammation protection through the inhibition of NF-κB activation in the mice. Together, our data reveal that quercetagitrin possesses the potential to further develop as a therapeutic medicine for AD and other tauopathies.

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Class IIa histone deacetylase s (HDAC) have been shown to drive innate immune cell-mediated inflammation in the peripheral system, but their roles in cerebral inflammatory responses remain largely unknown. Here, we elucidate that HDAC7 is selectively elevated in lipopolysaccharide (LPS)-challenged astrocytes both in vivo and in vitro. We identify that HDAC7 binds to the inhibitory kappa B kinase (IKK) to promote IKKα and IKKβ deacetylation and subsequent activation, leading to the activation of nuclear factor κB (NF-κB). Astrocyte-specific overexpression of HDAC7 results in NF-κB activation, pro-inflammatory gene upregulation and anxiety-like behaviors in mice, while downregulating HDAC7 reserves LPS-induced NF-κB activation and inflammatory responses. Furthermore, pharmacological inhibition of HDAC7 by a class IIa HDAC inhibitor attenuates LPS-induced NF-κB activation, neuroinflammation and anxiety-like disorders both in vivo and in vitro. Together, our data reveal a novel mechanism of HDAC7 in astroglial inflammation and suggest that targeting HDAC7 could be a potential therapeutic strategy for the treatment of anxiety and other neuroinflammation-related diseases.