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BACE1 inhibition more effectively suppresses initiation than progression of ?-amyloid pathology.

ABSTRACT: BACE1 is the rate-limiting protease in the production of synaptotoxic ?-amyloid (A?) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early ?-amyloid pathology. The longitudinal approach allowed to assess the kinetics of individual plaques and associated presynaptic pathology, before and throughout treatment. BACE1 inhibition could not halt but slow down progressive ?-amyloid deposition and associated synaptic pathology. Notably, the data revealed that the initial process of plaque formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. This finding of particular susceptibility of plaque formation has profound implications to achieve optimal therapeutic efficacy for the prospective treatment of AD.

SUBMITTER: Peters F

PROVIDER: S-EPMC5904228 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology.

Peters Finn F Salihoglu Hazal H Rodrigues Eva E Herzog Etienne E Blume Tanja T Filser Severin S Dorostkar Mario M Shimshek Derya R DR Brose Nils N Neumann Ulf U Herms Jochen J

Acta neuropathologica 20180111 5

BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact ...[more]

PMID: 29327084

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Project description:IntroductionNeuroinflammation and metabolic dysfunction are early alterations in Alzheimer's disease (AD) brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in AD patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.MethodsWe used Luminex XMAP technology to quantify hippocampal cytokine concentrations in the 5xFAD mouse model of AD at milestone timepoints in disease development. We used partial least squares regression to build cytokine signatures predictive of disease progression, as compared to healthy aging in wild-type littermates. We applied the disease-defining cytokine signature to wild-type primary neuron cultures and measured downstream changes in gene expression using the NanoString nCounter system and mitochondrial function using the Seahorse Extracellular Flux live-cell analyzer.ResultsWe identified a pattern of up-regulated IFNγ, IP-10/CXCL10, and IL-9 as predictive of advanced disease. When healthy neurons were exposed to these cytokines in proportions found in diseased brain, gene expression of mitochondrial electron transport chain complexes, including ATP synthase, was suppressed. In live cells, basal and maximal mitochondrial respiration were impaired following cytokine stimulation.ConclusionsWe identify a pattern of cytokine secretion predictive of progressing amyloid-β pathology in the 5xFAD mouse model of AD that reduces expression of mitochondrial electron transport complexes and impairs mitochondrial respiration in healthy neurons. We establish a mechanistic link between disease-specific immune cues and impaired neuronal metabolism, potentially causing neuronal vulnerability and susceptibility to degeneration in AD.Supplementary informationThe online version contains supplementary material available at 10.1007/s12195-023-00782-y.

Dataset Information

BACE1 inhibition more effectively suppresses initiation than progression of ?-amyloid pathology.

Publications

BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology.

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