S 24795 Limits β-Amyloid–α7 Nicotinic Receptor Interaction and Reduces Alzheimer's Disease-Like Pathologies

Wang, Hoau-Yan; Bakshi, Kalindi; Shen, Changpeng; Frankfurt, Maya; Trocmé-Thibierge, Caryn; Morain, Philippe

doi:10.1016/j.biopsych.2009.09.031

Cited by 48 publications

(44 citation statements)

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“…Mice anesthetized with 30 mg/kg sodium pentobarbital intraperitoneally were placed in a mouse stereotaxic surgery apparatus, as described previously (Wang et al, 2010). Mice receiving 7-day continuous ICV A␤ 42 infusion were implanted with a minipump (Alzet) that delivers 0.1 l/h through a surgical glue-secured cannula placed in the left ventricle at the following coordinates: anteroposterior from bregma, 3.0 mm; lateral, 1.0 mm; horizontal, 3.0 mm.…”

Section: Methodsmentioning

confidence: 99%

“…Using an established method (Wang et al, , 2010, tau proteins in synaptosomes from ICV A␤ 42 -infused mice were immunoprecipitated with immobilized anti-tau (SC-65865), which does not discriminate between phosphorylation states. The levels of phosphorylated tau (pSer 202 tau, pThr 231 tau and pThr 181 tau) and total tau precipitated (loading controls) were assessed by Western blotting using antibodies specific to each individual phosphoepitope and the anti-tau, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Because the level of voltage-gated Ca 2ϩ channel activity indicates the integrity of the cells, K ϩ -depolarization mediated Ca 2ϩ influx was used to assess the effect of PTI-125 on A␤ 42 -induced cell death, dysfunction, or both in treated mice and in postmortem tissues. As described previously (Wang et al, 2010), brain synaptosomes (50 -100 g) were incubated at 37°C for 5 min in oxygenated 1.2 mM (␣7nAChR and K ϩ ) or 0.3 mM Mg 2ϩ containing K-R (low Mg 2ϩ K-R [LMKR] for NMDAR) con- Figure 1. A, Continuous ICV A␤ 42 infusion for 1 week increased FLNA association with ␣7nAChR, and twice-daily intraperitoneal injections of PTI-125 for 2 weeks significantly reduced this interaction.…”

Section: Methodsmentioning

confidence: 99%

“…Eight-week-old male and female E129 mice (30 -35 g) from Taconic were maintained on a 12 h light/dark cycle with food and water. All animal procedures comply with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the City College of New York Animal Care and Use Committee.Mice anesthetized with 30 mg/kg sodium pentobarbital intraperitoneally were placed in a mouse stereotaxic surgery apparatus, as described previously (Wang et al, 2010). Mice receiving 7-day continuous ICV A␤ 42 infusion were implanted with a minipump (Alzet) that delivers 0.1 l/h through a surgical glue-secured cannula placed in the left ventricle at the following coordinates: anteroposterior from bregma, 3.0 mm; lateral, 1.0 mm; horizontal, 3.0 mm.…”

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confidence: 99%

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Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

Wang¹,

Bakshi²,

Frankfurt³

et al. 2012

Journal of Neuroscience

119

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PTI-125 is a novel compound demonstrating a promising new approach to treating IntroductionAlzheimer's disease (AD) represents one of the greatest health care burdens, affecting 35 million persons worldwide and an estimated 115 million persons by 2050 (Wimo and Prince, 2010). AD is a devastating dementia that first presents as progressive memory loss and later can include neuropsychiatric symptoms. Diagnosis is confirmed at autopsy by amyloid deposits and neurofibrillary tangles (NFTs) containing the microtubuleassociated protein tau. This neuropathology is estimated to precede symptoms by 10 years (Trojanowski et al., 2010). Current AD treatment is limited to acetylcholinesterase inhibitors, with mild and short-lived cognitive enhancement, and memantine, an NMDAR antagonist that may delay some later stage symptoms.Amyloid-␤ (A␤), in particular A␤ 42 , is commonly recognized as the principal causative agent in AD, though its mechanism is debated. Cognitive impairment and the magnitude of synaptic deficit in the AD brain are more highly correlated with soluble A␤ than with the abundance of amyloid plaques, suggesting that soluble A␤ inflicts synaptic impairment (Naslund et al., 2000). Robust evidence demonstrates that soluble A␤ elicits a toxic signaling cascade by the ␣7-nicotinic acetylcholine receptor (␣7nAChR), leading to impaired synaptic activities, intraneuronal A␤ 42 aggregates, and cognitive deficits (Liu et al., 2001;Pettit et al., 2001;Chen et al., 2006;Dziewczapolski et al., 2009;Wang et al., 2009). This aberrant signaling activates the kinases ERK2 and JNK1, which phosphorylate tau, leading to the formation of NFTs .A␤ 42 binds ␣7nAChR with femtomolar affinity (Wang et al., 2000a,b); therefore, to prevent A␤ 42 -induced ␣7nAChR toxic signaling, anti-A␤ therapies must either compete with this extremely high-affinity interaction or essentially eliminate all A␤ 42 . After the initial femtomolar interaction, numerous A␤ 42 molecules bind the receptor, eventually causing internalization and amyloid plaques. These additional A␤ 42 molecules appear to bind at a lower (picomolar) affinity (Wang et al., 2009); hence, it is possible to remove sufficient amounts of A␤ 42 to prevent plaque formation without any impact on the toxic signaling by the highaffinity A␤ 42 -␣7nAChR interaction. Furthermore, pharmacotherapies aiming to prevent A␤ 42 binding to ␣7nAChRs by directly targeting the receptor could, unfortunately, alter ␣7nAChR sensitivity or cell surface expression, especially if they surpass subpicomolar affinity. Alternative strategies to reduce A␤ 42 signaling by ␣7nAChR are needed.We show here that A␤ 42 toxic signaling requires the recruitment of the scaffolding protein filamin A (FLNA), which otherwise has very low levels of association with ␣7nAChR. Filamins are large cytoplasmic proteins best known for crosslinking actin but increasingly implicated in cell signaling (Stossel et al., 2001 A␤-induced FLNA recruitment to ␣7nAChRs and to reduce A␤ 42 signaling. PTI-125 decreases A␤ 42 affinity for ␣7nAC...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

Wang¹,

Bakshi²,

Frankfurt³

et al. 2012

Journal of Neuroscience

119

View full text Add to dashboard Cite

show abstract

“…Aβ 42 dose-dependently activates tau kinases to persistently phosphorylate tau at the three proline-directed sites, resulting in elevated hyperphosphorylated tau in neurofibrillary tangles. This Aβ-driven tau hyperphosphorylation can also be blocked by the α7nAChR antagonist α-bungarotoxin o r o t h e r α7n A C h R l i g a n d s i f a d m i n i s t e r e d prophylactically [32][33][34][35] . The hyperphosphorylation of tau renders it dysfunctional, alters its cellular distribution and disrupts axonal/dendritic transport, leading to neurofibrillary lesions, dendritic breakdown, and ultimately, neurofibrillary tangles [27] .…”

Section: Aβ Signaling Via α7nachr To Hyperphosphorylate Taumentioning

confidence: 99%

Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease

Burns¹,

Wang²

2017

Self Cite

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Alzheimer's disease (AD) is a neurodegenerative disease with proteopathy characterized by abnormalities in amyloid beta (Aβ) and tau proteins. Defective amyloid and tau propagate and aggregate, leading to eventual amyloid plaques and neurofibrillary tangles. New data show that a third proteopathy, an altered conformation of the scaffolding protein filamin A (FLNA), is critically linked to the amyloid and tau pathologies in AD. Altered FLNA is pervasive in AD brain and without apparent aggregation. In a striking interdependence, altered FLNA is both induced by Aβ and required for two prominent pathogenic signaling pathways of Aβ. Aβ monomers or small oligomers signal via the α7 nicotinic acetylcholine receptor (α7nAChR) to activate kinases that hyperphosphorylate tau to cause neurofibrillary lesions and formation of neurofibrillary tangles. Altered FLNA also enables a persistent activation of toll-like-receptor 4 (TLR4) by Aβ, leading to excessive inflammatory cytokine release and neuroinflammation. The novel AD therapeutic candidate PTI-125 binds and reverses the altered FLNA conformation to prevent Aβ's signaling via α7nAChR and aberrant activation of TLR4, thus reducing multiple AD-related neuropathologies. As a regulator of Aβ's signaling via α7nAChR and TLR4, altered FLNA represents a novel AD therapeutic target. Key words:Proteopathy, hyperphosphorylation, α7 nicotinic acetylcholine receptor, toll-like receptor 4, neuroinflammation, PTI-125 ABSTRACTArticle history:

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Targeting α7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development

Burns

Pei

Wang

2023

Drug Development Research

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The decades‐old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the α7 nicotinic acetylcholine receptor (α7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid β1‐42 (Aβ42) was shown to bind α7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau‐containing tangles. Multiple biopharmaceutical companies explored α7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting α7nAChR proved to be a drug development challenge. The ultra‐high‐affinity interaction between Aβ42 and α7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of α7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug‐related toxicities. As alternatives, proteins interacting with α7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with α7nAChR was shown to be critical to Aβ42's toxic signaling via α7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A–α7nAChR interaction, reduces Aβ42's high‐affinity binding to α7nAChR, and suppresses Aβ42's toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease‐modifying treatment for AD.

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S 24795 Limits β-Amyloid–α7 Nicotinic Receptor Interaction and Reduces Alzheimer's Disease-Like Pathologies

Cited by 48 publications

References 46 publications

Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A

Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease

Targeting α7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development

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