Dissociating β-Amyloid from α7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes α7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer's Disease Brain

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

“…These assessments used previously described coimmunoprecipitation methods (Wang et al, 2009). Two hundred micrograms of synaptosomes from either postmortem brain slices or prefrontal cortex or hippocampus of treated mice were pelleted by centrifugation, solubilized by brief sonication in 250 l of immunoprecipitation buffer (containing, in mM: 25 HEPES, pH 7.5, 200 NaCl, 1 EDTA, 50 g/ml leupeptin, 10 g/ml aprotinin, 2 g/ml soybean trypsin inhibitor, 0.04 PMSF, 5 NaF, 1 sodium vanadate, 0.5 ␤-glycerophosphate, and 0.1% 2-mercaptoethanol containing 0.5% digitonin, 0.2% sodium cholate, and 0.5% NP-40) and incubated at 4°C with end-to-end shaking for 1 h. After dilution with 750 l of ice-cold immunoprecipitation buffer and centrifugation (4°C) to remove insoluble debris, the FLNA-␣7nAChR/TLR4 and A␤ 42 -␣7nAChR complexes in the lysate were isolated by immunoprecipitation with 16 h incubation at 4°C with respective rabbit anti-FLNA (1 g) and anti-A␤ 42 antibodies (1 g) immobilized on protein A-conjugated agarose beads.…”

“…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.…”

“…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 .…”

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

“…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] .…”

Alzheimer's Disease and Prion Protein

“…The cellular mechanisms of Aβ oligomer-mediated neurotoxicity are poorly understood. Recent evidence indicate that the Aβ oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs) (22,24,25), may bind to a surface receptor on neurons, thereby initiating signaling transduction pathways that lead to synaptic dysfunction and neuronal death (26)(27)(28)(29). One interesting receptor for Aβ oligomers so far identified is the cellular prion protein (PrP C ) (30), which is a cell membrane glycoprotein ubiquitously expressed but enriched in the brain.…”