ABSTRACT
The ß-site amyloid-ß protein precursor (AßPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-ß peptide (Aß) from AßPP, one of the major pathways in Alzheimer's disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers. Overall, BACE1 CSF levels showed strong correlations to all downstream AD markers investigated. This is the first reported finding that shows BACE1 levels in CSF were well correlated to its end product Aß1 - 42. As previously described, BACE1 levels were strongly correlated to total-tau and phosphorylated tau levels in CSF. Generally, chronic BACE inhibition did not influence BACE1 CSF protein levels. Follow-up studies including early-stage AD pathophysiology and prodromal AD patients will help to understand the importance of measuring BACE1 routinely in daily clinical practice and AD clinical trials.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/cerebrospinal fluid , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Protease Inhibitors/therapeutic use , tau Proteins/cerebrospinal fluid , Aged , Alzheimer Disease/cerebrospinal fluid , Apolipoprotein E4/genetics , Biomarkers/cerebrospinal fluid , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Phosphorylation/drug effects , Protease Inhibitors/adverse effects , Protease Inhibitors/pharmacokineticsABSTRACT
Understanding differences in Alzheimer's disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-ß (Aß)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aß deposition in brain. However, the relevance of CSF Aß levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-ß protein precursor (AßPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aß42 levels and cognitive performance in young to middle-aged dogs (1.5-7 years old). Additionally, CSF sAßPPα and sAßPPß were measured to evaluate AßPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aß42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aß concentrations coincided with low or high sAßPPα, sAßPPß, and CXCL-1 levels, respectively. Dogs with high Aß concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aß concentrations. Our data support the hypothesis that high levels of CSF Aß in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer's disease pathology progression.
Subject(s)
Aging/cerebrospinal fluid , Aging/psychology , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Protein Precursor/cerebrospinal fluid , Cognitive Dysfunction/cerebrospinal fluid , Dog Diseases/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Animals , Biomarkers/cerebrospinal fluid , Chemokine CXCL1/cerebrospinal fluid , Choice Behavior , Cognition , Discrimination, Psychological , Dogs , Female , Male , Neuropsychological Tests , Reversal Learning , RewardABSTRACT
OBJECTIVES: Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ-54861911, were assessed after single and multiple dosing in healthy participants. METHODS: Two randomized, placebo-controlled, double-blind studies were performed using single and multiple ascending JNJ-54861911 doses (up to 14 days) in young and elderly healthy participants. Regular blood samples and frequent CSF samples, up to 36 hours after last dose, were collected to assess the pharmacokinetic and pharmacodynamic (Aß, sAPPα,ß,total levels) profiles of JNJ-54861911. RESULTS: JNJ-54861911 was well-tolerated, adverse events were uncommon and unrelated to JNJ-54861911. JNJ-54861911 showed dose-proportional CSF and plasma pharmacokinetic profiles. Plasma- and CSF-Aß and CSF-sAPPß were reduced in a dose-dependent manner. Aß reductions (up to 95%) outlasted exposure to JNJ-54861911. APOE ε4 carrier status and baseline Aß levels did not influence Aß/sAPPß reductions. CONCLUSION: JNJ-54861911, a potent brain-penetrant BACE1 inhibitor, achieved high and stable Aß reductions after single and multiple dosing in healthy participants.
