Genetic Variation in the α7 Nicotinic Acetylcholine Receptor is Associated with Delusional Symptoms in Alzheimer’s Disease

2008 ◽  
Vol 10 (4) ◽  
pp. 377-384 ◽  
Author(s):  
Robyn Carson ◽  
David Craig ◽  
Dominic Hart ◽  
Stephen Todd ◽  
Bernadette McGuinness ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variation ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine

PTI-125 REDUCES BIOMARKERS OF ALZHEIMER’S DISEASE IN PATIENTS

2020 ◽  
pp. 1-9
Author(s):  
H.-Y. Wang ◽  
Z. Pei ◽  
K.-C. Lee ◽  
E. Lopez-Brignoni ◽  
B. Nikolov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Filamin A ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine

BACKGROUND: The most common dementia worldwide, Alzheimer’s disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aβ1–42, and increases in total tau and phosphorylated tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer’s disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer’s disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aβ42’s toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aβ-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A’s linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aβ42’s activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer’s disease brain. OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A’s altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aβ42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4. DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study. SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application. PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer’s disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aβ42 ratio ≥0.30. INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days. MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer’s disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aβ42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1β and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aβ42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition. RESULTS: Consistent with the drug’s mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer’s disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aβ42’s signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aβ42 increased slightly – a desirable result because low Aβ42 indicates Alzheimer’s disease. This increase is consistent with PTI-125’s 1,000-fold reduction of Aβ42’s femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A’s conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aβ42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1. CONCLUSIONS: PTI-125 significantly reduced biomarkers of Alzheimer’s disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.

P3-209: Genetic variation in the alpha 7 nicotinic acetylcholine receptor is associated with delusional symptoms in Alzheimer's disease

2008 ◽  
Vol 4 ◽  
pp. T582-T582
Author(s):  
Robyn Carson ◽  
David Craig ◽  
Dominic Hart ◽  
Janet A. Johnston ◽  
Francis A. O'Neill ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variation ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Alpha 7

Role of Aβ and the α7 nicotinic acetylcholine receptor in regulating synaptic plasticity in Alzheimer's disease

2003 ◽  
Vol 10 (5-6) ◽  
pp. 401-404
Author(s):  
David H. Small ◽  
Lisa R. Fodero ◽  
Dusan Losic ◽  
Cindy Chu ◽  
Marie-Isabel Aguilar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine
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