Attenuation of Pb-induced Aβ generation and autophagic dysfunction via activation of SIRT1: Neuroprotective properties of resveratrol

β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aβ degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aβ production. Conversely, overexpression of PKCδ increases BACE1 expression and Aβ generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aβ levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin-1 with an exon 9 deletion–transgenic AD mouse model. Our study indicates that PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics.

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Genipin Attenuates Tau Phosphorylation and Aβ Levels in Cellular Models of Alzheimer's Disease

10.21203/rs.3.rs-309753/v1 ◽

2021 ◽

Author(s):

Meiting Li ◽

Nan Cai ◽

Liang Gu ◽

Lijun Yao ◽

Decheng Bi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Tau Phosphorylation ◽

Brain Disorder ◽

Cellular Models ◽

Aβ Generation ◽

Aβ Production

Abstract Alzheimer’s disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules are considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

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Enhanced amyloid-β generation by γ-secretase complex in DRM microdomains with reduced cholesterol levels

Human Molecular Genetics ◽

10.1093/hmg/ddz297 ◽

2019 ◽

Vol 29 (3) ◽

pp. 382-393 ◽

Cited By ~ 2

Author(s):

Saori Hata ◽

Anqi Hu ◽

Yi Piao ◽

Tadashi Nakaya ◽

Hidenori Taru ◽

...

Keyword(s):

Cultured Cells ◽

Late Onset ◽

Senile Plaques ◽

Amyloid Β ◽

Cholesterol Content ◽

Amyloid Β Protein ◽

Tissue Samples ◽

Β Protein ◽

Aβ Generation ◽

Carboxy Terminal

Abstract A neuropathologic hallmark of Alzheimer’s disease (AD) is the presence of senile plaques that contain neurotoxic amyloid-β protein (Aβ) species, which are generated by the cleavage of amyloid β-protein precursor by secretases such as the γ-secretase complex, preferentially located in detergent-resistant membrane (DRM) regions and comprising endoproteolysed amino- and carboxy-terminal fragments of presenilin, nicastrin, anterior pharynx defective 1 and presenilin enhancer 2. Whereas some of familial AD patients harbor causative PSEN mutations that lead to more generation of neurotoxic Aβ42, the contribution of Aβ generation to sporadic/late-onset AD remains unclear. We found that the carboxy-terminal fragment of presenilin 1 was redistributed from DRM regions to detergent-soluble membrane (non-DRM) regions in brain tissue samples from individuals with sporadic AD. DRM fractions from AD brain sample had the ability to generate significantly more Aβ and had a lower cholesterol content than DRM fractions from non-demented control subjects. We further demonstrated that lowering the cholesterol content of DRM regions from cultured cells contributed to the redistribution of γ-secretase components and Aβ production. Taken together, the present analyses suggest that the lowered cholesterol content in DRM regions may be a cause of sporadic/late-onset AD by enhancing overall Aβ generation.

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Investigating the contribution of astrocytic cholesterol transport in neuronal Aβ generation using human-induced pluripotent stem cells

IBRO Reports ◽

10.1016/j.ibror.2019.07.1186 ◽

2019 ◽

Vol 6 ◽

pp. S373

Author(s):

Woojin Jeong ◽

Hyein Lee ◽

Jinsoo Seo

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Cholesterol Transport ◽

Induced Pluripotent ◽

Aβ Generation

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3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice

Journal of Experimental Medicine ◽

10.1084/jem.20181035 ◽

2019 ◽

Vol 216 (2) ◽

pp. 279-293 ◽

Cited By ~ 14

Author(s):

Divna Lazic ◽

Abhay P. Sagare ◽

Angeliki M. Nikolakopoulou ◽

John H. Griffin ◽

Robert Vassar ◽

...

Keyword(s):

Protein C ◽

Early Stage ◽

Activated Protein C ◽

Amyloid Β ◽

Transcriptional Inhibition ◽

Model Of Alzheimer’S Disease ◽

Prevention Therapy ◽

A Cell ◽

Aβ Generation ◽

5Xfad Mice

3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer’s disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-β (Aβ) deposits by 40–50%, which is mediated through NFκB–dependent transcriptional inhibition of BACE1, resulting in blockade of Aβ generation in neurons overexpressing human Aβ-precursor protein. Consistent with reduced Aβ deposition, 3K3A-APC normalized hippocampus-dependent behavioral deficits and cerebral blood flow responses, improved cerebrovascular integrity, and diminished neuroinflammatory responses. Our data suggest that 3K3A-APC holds potential as an effective anti-Aβ prevention therapy for early-stage AD.

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