Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer’s disease

Aumont, Étienne; Tremblay, Cyntia; Levert, Stéphanie; Bennett, David A.; Calon, Frédéric; Leclerc, Nicole

doi:10.3389/fnagi.2022.1038343

Cited by 4 publications

(5 citation statements)

References 53 publications

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“…Therefore, Filamin A regulation in platelets from mice over‐expressing Dyrk1A would not be link to SRF/MKL1A pathway. Filamin A is also a key partner in Aβ and Tau pathological processes in AD 54,55 …”

Section: Discussionmentioning

confidence: 99%

Over‐expression of Dyrk1A affects bleeding by modulating plasma fibronectin and fibrinogen level in mice

Postic,

Solarz,

Loubière

et al. 2023

J Cellular Molecular Medi

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Down syndrome is the most common chromosomal abnormality in humans. Patients with Down syndrome have hematologic disorders, including mild to moderate thrombocytopenia. In case of Down syndrome, thrombocytopenia is not associated with bleeding, and it remains poorly characterized regarding molecular mechanisms. We investigated the effects of overexpression of Dyrk1A, an important factor contributing to some major Down syndrome phenotypes, on platelet number and bleeding in mice. Mice overexpressing Dyrk1A have a decrease in platelet number by 20%. However, bleeding time was found to be reduced by 50%. The thrombocytopenia and the decreased bleeding time observed were not associated to an abnormal platelet receptors expression, to a defect of platelet activation by ADP, thrombin or convulxin, to the presence of activated platelets in the circulation or to an abnormal half‐life of the platelets. To propose molecular mechanisms explaining this discrepancy, we performed a network analysis of Dyrk1A interactome and demonstrated that Dyrk1A, fibronectin and fibrinogen interact indirectly through two distinct clusters of proteins. Moreover, in mice overexpressing Dyrk1A, increased plasma fibronectin and fibrinogen levels were found, linked to an increase of the hepatic fibrinogen production. Our results indicate that overexpression of Dyrk1A in mice induces decreased bleeding consistent with increased plasma fibronectin and fibrinogen levels, revealing a new role of Dyrk1A depending on its indirect interaction with these two proteins.

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Section: Discussionmentioning

confidence: 99%

Over‐expression of Dyrk1A affects bleeding by modulating plasma fibronectin and fibrinogen level in mice

Postic,

Solarz,

Loubière

et al. 2023

J Cellular Molecular Medi

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“…Complementing the conformational change of FLNA in AD implied by the shift in isoelectric focusing point, another group has recently shown higher levels of insoluble versus soluble FLNA in prodromal AD and AD dementia compared to healthy control and preclinical AD (Aumont et al, 2022). Although these data again indicate an AD-related change in FLNA, exactly how and when FLNA changes in AD is yet to be elucidated.…”

Section: Filamin Amentioning

confidence: 99%

“…The recruitment of FLNA tightens the whole complex through the membrane so that the conformation of FLNA is altered and Aβ 42 binds with ultra-high affinity, continuing to pile onto α7nAChR (Nagele et al, 2002;Wang et al, 2012;Wang, Lee, D'andrea et al, 2000). FLNA's altered conformation is suggested by a shift in isoelectric focusing point (Wang et al, 2017) and insolubility (Aumont et al, 2022). The Aβ 42 -α7nAChR-FLNA complex activates kinases ERK and JNK1 to hyperphosphorylate tau (Wang et al, 2012(Wang et al, , 2017, rendering tau incapable of stabilizing microtubules.…”

Section: Filamin Amentioning

confidence: 99%

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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“…Best known for cross-linking actin via the N-terminal domain to provide structure and motility, FLNA also serves as a scaffold for channels, receptors, signaling molecules and even transcription factors, illustrating a role beyond structure [ 11 , 14 , 15 ]. FLNA is highly expressed in the brain, and its protein interactions are regulated by mechanical forces, phosphorylation, cleavage and other factors [ 11 , 13 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…A region of FLNA unfolds under forces as low as 10 pN [ 17 ], and stress-induced conformational changes have been hypothesized to play a direct role in signaling, either by disrupting existing interactions or inducing new ones [ 18 ]. In an altered conformation implied by a shift in isoelectric focusing point [ 8 , 10 , 19 ] and a change in solubility [ 16 ], FLNA appears to be a critical and deviant receptor-associated protein underlying multiple facets of AD pathology [ 9 , 10 ]. Specifically, deviant FLNA linkages are critical to Aβ 42 -induced tau hyperphosphorylation, leading to neurodegeneration, and to Aβ 42 -induced activation of TLR4, leading to neuroinflammation [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer’s Disease

Wang,

Cecon,

Dam

et al. 2023

IJMS

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Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer’s disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs in AD. This drug action disrupts FLNA’s aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), thereby blocking soluble amyloid beta1–42 (Aβ42)’s signaling via α7nAChR that hyperphosphorylates tau. Here, we aimed to clarify simufilam’s mechanism. We now show that simufilam reduced Aβ42 binding to α7nAChR with a 10-picomolar IC50 using time-resolved fluorescence resonance energy transfer (TR-FRET), a robust technology to detect highly sensitive molecular interactions. We also show that FLNA links to multiple inflammatory receptors in addition to Toll-like receptor 4 (TLR4) in postmortem human AD brains and in AD transgenic mice: TLR2, C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 5 (CCR5), and T-cell co-receptor cluster of differentiation 4 (CD4). These aberrant FLNA linkages, which can be induced in a healthy control brain by Aβ42 incubation, were disrupted by simufilam. Simufilam reduced inflammatory cytokine release from Aβ42-stimulated human astrocytes. In the AD transgenic mice, CCR5–G protein coupling was elevated, indicating persistent activation. Oral simufilam reduced both the FLNA–CCR5 linkage and the CCR5–G protein coupling in these mice, while restoring CCR5′s responsivity to C-C chemokine ligand 3 (CCL3). By disrupting aberrant FLNA–receptor interactions critical to AD pathogenic pathways, simufilam may promote brain health.

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Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer’s disease

Cited by 4 publications

References 53 publications

Over‐expression of Dyrk1A affects bleeding by modulating plasma fibronectin and fibrinogen level in mice

Over‐expression of Dyrk1A affects bleeding by modulating plasma fibronectin and fibrinogen level in mice

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

Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer’s Disease

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