Targeting Neuroinflammation to Treat Alzheimer’s Disease

Abstract

Over the past few decades, research on Alzheimer’s disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that—upon engagement of pattern recognition receptors—induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.

Knockdown of cathepsin D protects dopaminergic neurons against neuroinflammation‐mediated neurotoxicity through inhibition of NF‐κB signalling pathway in Parkinson's disease model

“…It has been documented that, the activated microglia can secrete large amounts of inflammatory mediators, such as iNOS, TNF‐α, and IL‐1β in the brain tissues, which are generally considered prominent factors leading to neuroinflammation and neurotoxicity in neurodegenerative diseases, such as AD and PD . In addition to inflammatory mediators, the expression of CathD has been reported to be upregulated in the activated microglia .…”

Meta-analysis of the human brain transcriptome identifies heterogeneity across human AD coexpression modules robust to sample collection and methodological approach

“…Several systems-level analyses of human AD brain have been previously reported (Allen et al, 2018a, 2018b; Lu et al, 2014; Mostafavi et al, 2018; Seyfried et al, 2017; Zhang et al, 2013a). The importance of neuroinflammation in AD has been described across these (Patrick et al, 2017; Zhang et al, 2013a) and also from genetic studies (Carrasquillo et al, 2017; Efthymiou and Goate, 2017; Guerreiro et al, 2013; Jin et al, 2015; Jonsson et al, 2013; Raj et al, 2014; Sims et al, 2017), supporting a major focus on this pathway for therapeutic development as is currently underway (Ardura-Fabregat et al, 2017). In addition to neuroinflammation, other molecular pathways have been identified from systems biology studies of both RNA and protein abundance including multiple processes related to oligodendrocytic functions such as myelination (Allen et al, 2018a; McKenzie et al, 2017; Mostafavi et al, 2018; Seyfried et al, 2017).…”

NGF steers microglia toward a neuroprotective phenotype

“…The idea of harnessing the CNS immune system—the natural scavengers of the brain—to boost neuroprotection in the brain is intriguing, especially when tackling diseases marked by loss of proteostasis such as Alzheimer's disease (AD; Ardura‐Fabregat et al, ). In the search of neuroprotective agents against neurodegeneration, neurotrophins have been historically considered as potential therapeutic candidates, mostly due to their actions on neuronal targets.…”