ABSTRACT
BACKGROUND: Alzheimer disease (AD) and depression often cooccur, and inhibition of phosphodiesterase-4 (PDE4) has been shown to ameliorate neurodegenerative illness. Therefore, we explored whether PDE4 inhibitor rolipram might also improve the symptoms of comorbid AD and depression. METHODS: APP/PS1/tau mice (10 months old) were treated with or without daily i.p. injections of rolipram for 10 days. The animal groups were compared in behavioral tests related to learning, memory, anxiety, and depression. Neurochemical measures were conducted to explore the underlying mechanism of rolipram. RESULTS: Rolipram attenuated cognitive decline as well as anxiety- and depression-like behaviors. These benefits were attributed at least partly to the downregulation of amyloid-ß, Amyloid precursor protein (APP), and Presenilin 1 (PS1); lower tau phosphorylation; greater neuronal survival; and normalized glial cell function following rolipram treatment. In addition, rolipram upregulated B-cell lymphoma-2 (Bcl-2) and downregulated Bcl-2-associated X protein (Bax) to reduce apoptosis; it also downregulated interleukin-1ß, interleukin-6, and tumor necrosis factor-α to restrain neuroinflammation. Furthermore, rolipram increased cAMP, PKA, 26S proteasome, EPAC2, and phosphorylation of ERK1/2 while decreasing EPAC1. CONCLUSIONS: Rolipram may mitigate cognitive deficits and depression-like behavior by reducing amyloid-ß pathology, tau phosphorylation, neuroinflammation, and apoptosis. These effects may be mediated by stimulating cAMP/PKA/26S and cAMP/exchange protein directly activated by cAMP (EPAC)/ERK signaling pathways. This study suggests that PDE4 inhibitor rolipram can be an effective target for treatment of comorbid AD and depression.
Subject(s)
Alzheimer Disease , Phosphodiesterase 4 Inhibitors , Mice , Animals , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Amyloid beta-Protein Precursor/pharmacology , Rolipram/pharmacology , Mice, Transgenic , Phosphodiesterase 4 Inhibitors/pharmacology , Neuroinflammatory Diseases , Presenilin-1/metabolism , Presenilin-1/pharmacology , Depression/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Memory Disorders/drug therapy , Apoptosis , Disease Models, AnimalABSTRACT
OBJECTIVES: Transauricular vagal nerve stimulation (taVNS) at 40 Hz attenuates hippocampal amyloid load in 6-month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, but it is unclear whether 40-Hz taVNS can improve cognition in these mice. Moreover, the underlying mechanisms are still unclear. MATERIALS AND METHODS: 6-month-old C57BL/6 (wild type [WT]) and APP/PS1 mice were subjected to 40-Hz taVNS. Novel Object Recognition and the Morris Water Maze were used to evaluate cognition. Hippocampal amyloid-ß (Aß)1-40, Aß1-42, pro-interleukin (IL)-1ß, and pro-IL-18 were measured using enzyme-linked immunosorbent assays. Hippocampal Aß42, purinergic 2X7 receptor (P2X7R), nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3), Caspase-1, IL-1ß, and IL-18 expression were evaluated by western blotting. Histologic assessments including immunofluorescence, immunohistochemistry, Nissl staining, and Congo red staining were used to assess microglial phagocytosis, neuroprotective effects, and Aß plaque load. RESULTS: 40-Hz taVNS improved spatial memory and learning in 6-month-old APP/PS1 mice but did not affect recognition memory. There were no effects on the cognitive behaviors of 6-month-old WT mice. taVNS at 40 Hz modulated microglia; significantly decreased levels of Aß1-40, Aß1-42, pro-IL-1ß, and pro-IL-18; inhibited Aß42, P2X7R, NLRP3, Caspase-1, IL-1ß, and IL-18 expression; reduced Aß deposits; and had neuroprotective effects in the hippocampus of 6-month-old APP/PS1 mice. These changes were not observed in 6-month-old WT mice. CONCLUSION: Our results show that 40-Hz taVNS inhibits the hippocampal P2X7R/NLRP3/Caspase-1 signaling and improves spatial learning and memory in 6-month-old APP/PS1 mice.
Subject(s)
Neuroprotective Agents , Vagus Nerve Stimulation , Mice , Animals , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Amyloid beta-Protein Precursor/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Interleukin-18/metabolism , Interleukin-18/pharmacology , Spatial Learning , Presenilin-1/genetics , Presenilin-1/metabolism , Presenilin-1/pharmacology , Caspase 1/metabolism , Caspase 1/pharmacology , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Mice, Inbred C57BL , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/pharmacology , Mice, Transgenic , Hippocampus/metabolismABSTRACT
Many efforts targeting amyloid-ß (Aß) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-Aß treatments through high-resolution light-sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to ß-secretase inhibitors, polythiophenes, or anti-Aß antibodies. Each treatment showed unique spatiotemporal Aß clearance, with polythiophenes emerging as a potent anti-Aß compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each Aß therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of Aß plaques. This may also contribute to the clinical trial failures of Aß-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.
Subject(s)
Alzheimer Disease , Microscopy , Mice , Animals , Mice, Transgenic , Amyloid beta-Peptides/metabolism , Alzheimer Disease/drug therapy , Brain/metabolism , Plaque, Amyloid/drug therapy , Disease Models, Animal , Amyloid beta-Protein Precursor , Presenilin-1/pharmacologyABSTRACT
Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1), a negative regulator of oligodendrocyte differentiation and myelination, is associated with cognitive function, and its expression is highly upregulated in Alzheimer's disease (AD) patients. Anti-LINGO-1 antibody treatment can effectively antagonize the negative regulatory effect of LINGO-1. In this study, we aim to assess the effect of anti-LINGO-1 antibody treatment on cognition and hippocampal oligodendrocytes in an AD transgenic animal model. First, 10-month-old male amyloid-ß (Aß) protein precursor (APP)/presenilin 1 (PS1) mice were administered anti-LINGO-1 antibody for 8 weeks. Then, learning and memory abilities were assessed with the Morris water maze (MWM) and Y-maze tests, and Aß deposition and hippocampal oligodendrocytes were investigated by immunohistochemistry, immunofluorescence, and stereology. We found that anti-LINGO-1 antibody alleviated the deficits in spatial learning and memory abilities and working and reference memory abilities, decreased the density of LINGO-1 positive cells, decreased Aß deposition, significantly increased the number of mature oligodendrocytes and the density of myelin, reversed the abnormal increases in the number of oligodendrocyte lineage cells and the densities of oligodendrocytes precursor cells in APP/PS1 mice. Our results provide evidence that LINGO-1 might be involved in the process of oligodendrocyte dysmaturity in the hippocampus of AD mice, and that antagonizing LINGO-1 can alleviate cognitive deficits in APP/PS1 mice and decrease Aß deposition and promote oligodendrocyte differentiation and maturation in the hippocampus of these mice. Our findings suggest that changes in LINGO-1 and oligodendrocytes in the hippocampus play important roles in the pathogenesis of AD and that antagonizing LINGO-1 might be a potential therapeutic strategy for AD.
Subject(s)
Alzheimer Disease , Hippocampus , Alzheimer Disease/pathology , Amyloid beta-Peptides , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Amyloid beta-Protein Precursor/pharmacology , Animals , Cognition , Disease Models, Animal , Hippocampus/metabolism , Humans , Male , Maze Learning , Mice , Mice, Transgenic , Oligodendroglia/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , Presenilin-1/pharmacologyABSTRACT
alpha-Synuclein is central in Parkinson's disease pathogenesis. Although initially alpha-synuclein was considered a purely intracellular protein, recent data suggest that it can be detected in the plasma and CSF of humans and in the culture media of neuronal cells. To address a role of secreted alpha-synuclein in neuronal homeostasis, we have generated wild-type alpha-synuclein and beta-galactosidase inducible SH-SY5Y cells. Soluble oligomeric and monomeric species of alpha-synuclein are readily detected in the conditioned media (CM) of these cells at concentrations similar to those observed in human CSF. We have found that, in this model, alpha-synuclein is secreted by externalized vesicles in a calcium-dependent manner. Electron microscopy and liquid chromatography-mass spectrometry proteomic analysis demonstrate that these vesicles have the characteristic hallmarks of exosomes, secreted intraluminar vesicles of multivesicular bodies. Application of CM containing secreted alpha-synuclein causes cell death of recipient neuronal cells, which can be reversed after alpha-synuclein immunodepletion from the CM. High- and low-molecular-weight alpha-synuclein species, isolated from this CM, significantly decrease cell viability. Importantly, treatment of the CM with oligomer-interfering compounds before application rescues the recipient neuronal cells from the observed toxicity. Our results show for the first time that cell-produced alpha-synuclein is secreted via an exosomal, calcium-dependent mechanism and suggest that alpha-synuclein secretion serves to amplify and propagate Parkinson's disease-related pathology.
Subject(s)
Calcium/metabolism , Exosomes/physiology , Multivesicular Bodies/pathology , alpha-Synuclein/genetics , alpha-Synuclein/metabolism , Analysis of Variance , Animals , Brefeldin A/pharmacology , Calcium/pharmacology , Cell Death/drug effects , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cell Survival/genetics , Cells, Cultured , Cerebral Cortex/cytology , Chromatography, High Pressure Liquid/methods , Culture Media, Conditioned/chemistry , Culture Media, Conditioned/pharmacology , Cytotoxicity Tests, Immunologic/methods , Dose-Response Relationship, Drug , Endocytosis/drug effects , Exosomes/ultrastructure , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hydrogen Peroxide/pharmacology , Immunoprecipitation/methods , Mass Spectrometry/methods , Microscopy, Confocal/methods , Microscopy, Electron, Transmission/methods , Molecular Weight , Multivesicular Bodies/drug effects , Multivesicular Bodies/ultrastructure , Nerve Tissue Proteins/metabolism , Neuroblastoma/pathology , Neuroblastoma/ultrastructure , Neurons/drug effects , Neurons/metabolism , Neurons/ultrastructure , Peptides/pharmacology , Piperidines/pharmacology , Presenilin-1/pharmacology , Protein Synthesis Inhibitors/pharmacology , Pyrazoles/pharmacology , Rats , Receptors, Transferrin/metabolism , Serum/metabolism , Subcellular Fractions/drug effects , Subcellular Fractions/metabolism , Subcellular Fractions/ultrastructure , Temperature , Transfection , beta-Galactosidase/genetics , beta-Galactosidase/metabolismABSTRACT
BACKGROUND: Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer's disease. OBJECTIVE: We aimed to shed light on the mode of action of masitinib in Alzheimer's disease. METHODS/RESULTS: We demonstrated here that chronic oral treatment of APPswe/PSEN1dE9 transgenic mice modeling Alzheimer's disease restored normal spatial learning performance while having no impacts on amyloid-ß loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPswe/PSEN1dE9 mice similarly rescued synaptic impairments. CONCLUSION: These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition.