Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models.

Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death-1 (PD1) checkpoint inhibition produces an IFN-γ-dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (): Nature Medicine, 22:135-137).

A digital enzyme-linked immunosorbent assay for ultrasensitive measurement of amyloid-β 1-42 peptide in human plasma with utility for studies of Alzheimer's disease therapeutics.

Background: Amyloid-β 1-42 peptide (Aβ) is associated with plaque formation in the brain of patients with Alzheimer's disease (AD). Pharmacodynamic studies of AD therapeutics that lower the concentrations of Aβ in peripheral blood require highly sensitive assays for its measurement. A digital enzyme-linked immunosorbent assay (ELISA) using single molecule array (Simoa) technology has been developed that provides improved sensitivity compared with conventional ELISA methods using the same antibody reagents.

β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage.

Introduction: The β-secretase enzyme, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory Aβ biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of Aβ1-34 together with increased Aβ5-40, suggesting that these Aβ species may be novel pharmacodynamic biomarkers in clinical trials.

Validation of assays for measurement of amyloid-β peptides in cerebrospinal fluid and plasma specimens from patients with Alzheimer's disease treated with solanezumab.

The aim of this study was to validate new assays for measurement of amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF) and plasma specimens in clinical studies of solanezumab according to current regulatory recommendations. Four assays based on the INNOTEST® β-AMYLOID(1-42) and prototype INNOTEST β-AMYLOID(1-40) kits were developed and validated. To render these assays 'solanezumab-tolerant', excess drug was added to calibrators, quality control, and test samples via a 2-fold dilution with kit diluent.

A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice.

Aβ Immunotherapy is a promising therapeutic approach for Alzheimer's disease. Preclinical studies demonstrate that plaque prevention is possible; however, the more relevant therapeutic removal of existing plaque has proven elusive. Monoclonal antibodies in development target both soluble and insoluble Aβ peptide.

ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo.

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain.

Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta.

Passive immunization with an antibody directed against the N terminus of amyloid beta (Abeta) has recently been reported to exacerbate cerebral amyloid angiopathy (CAA)-related microhemorrhage in a transgenic animal model. Although the mechanism responsible for the deleterious interaction is unclear, a direct binding event may be required. We characterized the binding properties of several monoclonal anti-Abeta antibodies to deposited Abeta in brain parenchyma and CAA.

Activation of caspase-3 alone is insufficient for apoptotic morphological changes in human neuroblastoma cells.

Activated caspase-3 is considered an important enzyme in the cell death pathway. To study the specific role of caspase-3 activation in neuronal cells, we generated a stable tetracycline-regulated SK-N-MC neuroblastoma cell line, which expressed a highly efficient self-activating chimeric caspase-3, consisting of the caspase-1 prodomain fused to the caspase-3 catalytic domain. Under expression-inducing conditions, we observed a time-dependent increase of processed caspase-3 by immunostaining for the active form of the enzyme, intracellular caspase-3 enzyme activity, as well as poly(ADP-ribose) polymerase (PARP) cleavage.