For decades, research on Alzheimer’s disease (AD) has focused on the two pathological hallmarks of the disease: amyloid plaques and neurofibrillary tangles. That reactive astrocytes and activated microglia decorate amyloid plaques in the cortex of individuals with AD dementia is another long known pathological feature of the AD brain. Yet the participation of these glial cells in the pathogenesis of the disease has been neglected for a long time. Only recently the role of glia in AD is gaining momentum as a topic of Research, fueled by the GWAS discovery of several risk loci in genes related to the innate immune system, and by the involvement of microglia and astrocytes in synaptic pruning and the modulation of synaptic activity in physiologic conditions.
Many questions remain unanswered. Is glial reaction against amyloid plaques protective or deleterious with respect to neurons and synapses? If it is deleterious, is it due to a gain of toxic function or to a loss of normal function? Does reactive glia represent a “second hit” to neurons and synapses after the primary damage caused by amyloid ß and tau? Is there a cross-talk between activated microglia and reactive astrocytes? What are the molecular pathways underlying the “activation” of these glial cells? Does this reaction have deleterious effects on astrocytes and microglia themselves? What is the natural history of glial cells in AD?
The advent of new tools will enable to answer some of these questions in the near future. Human induced pluripotent stem cells (hiPSCs), 3D cultures, and brain organoids will multiplex the possibilities of in vitro studies. New protocols now allow the acute isolation of microglia and astrocytes from postnatal mice and human brains with an unprecedented degree of purity. Recently developed RNA-seq technology allows deep sequencing of the transcriptome of even single cells. In vivo multiphoton microscopy has opened a window for the observation of the dynamics of glial cells in living mice. Selective genetic editing using brand new CRISPR/Cas9 technology will provide a unique opportunity to manipulate glial cells in vivo. New magnetic resonance techniques (i.e. spectroscopy, ultrasmall superparamagnetic iron oxide or USPIO nanoparticles) and PET radiotracers will allow the monitoring of glial responses in vivo in cognitively intact elderly subjects and across the AD clinical continuum.
Understanding the role of glia in AD could lead to a whole array of new molecular therapeutic targets that could complement current efforts to develop therapies directed against amyloid ß and tau. In the future, the effective treatment of AD may well consist of a rational polytherapy with drugs against amyloid ß, tau, and glial reaction, that would be tailored based on patient’s biomarker profile.
For decades, research on Alzheimer’s disease (AD) has focused on the two pathological hallmarks of the disease: amyloid plaques and neurofibrillary tangles. That reactive astrocytes and activated microglia decorate amyloid plaques in the cortex of individuals with AD dementia is another long known pathological feature of the AD brain. Yet the participation of these glial cells in the pathogenesis of the disease has been neglected for a long time. Only recently the role of glia in AD is gaining momentum as a topic of Research, fueled by the GWAS discovery of several risk loci in genes related to the innate immune system, and by the involvement of microglia and astrocytes in synaptic pruning and the modulation of synaptic activity in physiologic conditions.
Many questions remain unanswered. Is glial reaction against amyloid plaques protective or deleterious with respect to neurons and synapses? If it is deleterious, is it due to a gain of toxic function or to a loss of normal function? Does reactive glia represent a “second hit” to neurons and synapses after the primary damage caused by amyloid ß and tau? Is there a cross-talk between activated microglia and reactive astrocytes? What are the molecular pathways underlying the “activation” of these glial cells? Does this reaction have deleterious effects on astrocytes and microglia themselves? What is the natural history of glial cells in AD?
The advent of new tools will enable to answer some of these questions in the near future. Human induced pluripotent stem cells (hiPSCs), 3D cultures, and brain organoids will multiplex the possibilities of in vitro studies. New protocols now allow the acute isolation of microglia and astrocytes from postnatal mice and human brains with an unprecedented degree of purity. Recently developed RNA-seq technology allows deep sequencing of the transcriptome of even single cells. In vivo multiphoton microscopy has opened a window for the observation of the dynamics of glial cells in living mice. Selective genetic editing using brand new CRISPR/Cas9 technology will provide a unique opportunity to manipulate glial cells in vivo. New magnetic resonance techniques (i.e. spectroscopy, ultrasmall superparamagnetic iron oxide or USPIO nanoparticles) and PET radiotracers will allow the monitoring of glial responses in vivo in cognitively intact elderly subjects and across the AD clinical continuum.
Understanding the role of glia in AD could lead to a whole array of new molecular therapeutic targets that could complement current efforts to develop therapies directed against amyloid ß and tau. In the future, the effective treatment of AD may well consist of a rational polytherapy with drugs against amyloid ß, tau, and glial reaction, that would be tailored based on patient’s biomarker profile.
