The p38 mitogen activated protein kinase regulates β-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain

Ma, Kai; Lv, Jia; Yang, Weina; Chang, Ke-Wei; Hu, Xiaodan; Shi, Lili; Zhai, Wanying; Zong, Hang-Fan; Qian, Yi‐Hua

doi:10.1016/j.brainresbull.2017.11.006

Cited by 19 publications

(14 citation statements)

References 71 publications

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“…Mechanistic insights from the in vitro work suggests competitive binding between ACh and Aβ 1–42 to the α7 nAChR as both agonist and antagonist mitigates Aβ uptake. The α7 nAChR binds Aβ with high affinity [30] and internalizes Aβ into the endosomes/lysosomes and mitochondria [ 31 , 32 ]. Uptake of Aβ phosphorylates p38, induces apoptosis [31] and α7 nAChR agonists mitigate the Aβ-induced apoptosis in animal models [33] .…”

Section: Discussionmentioning

confidence: 99%

“…The α7 nAChR binds Aβ with high affinity [30] and internalizes Aβ into the endosomes/lysosomes and mitochondria [ 31 , 32 ]. Uptake of Aβ phosphorylates p38, induces apoptosis [31] and α7 nAChR agonists mitigate the Aβ-induced apoptosis in animal models [33] . Further studies are needed to elucidate the mechanistic link between receptor structure and Aβ binding with specifically designed studies incorporating genetic and pharmacological paradigms.…”

Section: Discussionmentioning

confidence: 99%

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CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

et al. 2020

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Background Cholinergic neuronal loss is one of the hallmarks of AD related neurodegeneration; however, preclinical promise of α7 nAChR drugs failed to translate into humans. CHRFAM7A , a uniquely human fusion gene, is a negative regulator of α7 nAChR and was unaccounted for in preclinical models. Methods Molecular methods: Function of CHRFAM7A alleles was studied in vitro in two disease relevant phenotypic readouts: electrophysiology and Aβ uptake. Genome edited human induced pluripotent stem cells (iPSC) were used as a model system with the human context. Double blind pharmacogenetic study: We performed double-blind pharmacogenetic analysis on the effect of AChEI therapy based on CHRFAM7A carrier status in two paradigms: response to drug initiation and DMT effect. Mini Mental Status Examination (MMSE) was used as outcome measure. Change in MMSE score from baseline was compared by 2-tailed T-test. Longitudinal analysis of clinical outcome (MMSE) was performed using a fitted general linear model, based on an assumed autoregressive covariance structure. Model independent variables included age, sex, and medication regimen at the time of the first utilized outcome measure (AChEI alone or AChEI plus memantine), APOE4 carrier status (0, 1 or 2 alleles as categorical variables) and CHRFAM7A genotype. Findings The direct and inverted alleles have distinct phenotypes. Functional CHRFAM7A allele classifies the population as 25% non-carriers and 75% carriers. Induced pluripotent stem cell (iPSC) models α7 nAChR mediated Aβ neurotoxicity. Pharmacological readout translates into both first exposure ( p = 0.037) and disease modifying effect ( p = 0.0048) in two double blind pharmacogenetic studies. Interpretation CHRFAM7A accounts for the translational gap in cholinergic strategies in AD. Clinical trials not accounting for this uniquely human genetic factor may have rejected drug candidates that would benefit 25% of AD. Reanalyses of the completed trials using this pharmacogenetic paradigm may identify effective therapy. Funding:

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

et al. 2020

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Section: Cholinergic and Mitochondrial Dysfunction In Admentioning

confidence: 99%

“…The significant upregulation of α7-nAChR at the nucleus basalis of Meynert in AD is possibly due to a compensatory effect from the blocking or disruption by Aβ, which maintains the cholinergic transmission [ 178 - 180 ]. The binding of Aβ to α7-nAchR on the cell membrane stimulates p38MAPK and Bax/Bal pathways to enhance mitochondrial membrane permeabilisation, which increases cyt c release and mitochondrial-dependent apoptosis [ 178 ]. On the other hand, agonistic cellular and mitochondrial α7-nAchR can attenuate the p38 MAPK cascade [ 178 ], thereby preventing the formation of VDAC and subsequent mPTP opening, as well as mitochondrial-induced apoptosis [ 181 ].…”

Section: Cholinergic and Mitochondrial Dysfunction In Admentioning

confidence: 99%

Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease

et al. 2020

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Besides extracellular deposition of amyloid beta and formation of phosphorylated tau in the brains of patients with Alzheimer's disease (AD), the pathogenesis of AD is also thought to involve mitochondrial dysfunctions and altered neurotransmission systems. However, none of these components can describe the diverse cognitive, behavioural, and psychiatric symptoms of AD without the pathologies interacting with one another. The purpose of this review is to understand the relationships between mitochondrial and neurotransmission dysfunctions in terms of (1) how mitochondrial alterations affect cholinergic and monoaminergic systems via disruption of energy metabolism, oxidative stress, and apoptosis; and (2) how different neurotransmission systems drive mitochondrial dysfunction via increasing amyloid beta internalisation, oxidative stress, disruption of mitochondrial permeabilisation, and mitochondrial trafficking. All these interactions are separately discussed in terms of neurotransmission systems. The association of mitochondrial dysfunctions with alterations in dopamine, norepinephrine, and histamine is the prospective goal in this research field. By unfolding the complex interactions surrounding mitochondrial dysfunction in AD, we can better develop potential treatments to delay, prevent, or cure this devastating disease.

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“…For example, a site on the wild‐type protein may be tightly regulated to function only under certain circumstances, but that site might become constitutively active due to misfolding. One of the best‐studied gain‐of‐function effects is the hyperactivation of kinases or phosphatases elicited by various mutant or otherwise abnormal proteins associated with neurodegenerative diseases (Cantuti Castelvetri et al, ; Kanaan et al, ; Ma et al, ; Morfini et al, ). A feature of gain‐of‐function toxicity is that very small amounts of the mutant protein can have negative effects far broader than expected based on the canonical functions of the wild‐type protein; the aberrant activation of a kinase is a good example of this.…”

Section: Gain‐of‐function Toxicitymentioning

confidence: 99%

New hypothesis for the etiology of SPAST‐based hereditary spastic paraplegia

2019

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Mutations of the SPAST gene are the chief cause of hereditary spastic paraplegia. Controversy exists in the medical community as to whether the etiology of the disease is haploinsufficiency or toxic gain‐of‐function properties of the mutant spastin proteins. In recognition of strong reasons that support each possible mechanism, here we present a novel perspective, based in part on new studies with mouse models and in part on the largest study to date on patients with the disease. We posit that haploinsufficiency does not cause the disease but makes the corticospinal tracts vulnerable to a second hit, which is usually the mutant spastin proteins but could also be proteins generated by mutations of other genes that may or may not cause the disease on their own.

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The p38 mitogen activated protein kinase regulates β-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain

Cited by 19 publications

References 71 publications

CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease

New hypothesis for the etiology of SPAST‐based hereditary spastic paraplegia

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