The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications

BACKGROUND: Astrocytes, also called astroglia, maintain homoeostasis of the brain by providing trophic and metabolic support to neurons. They recycle neurotransmitters, stimulate synaptogenesis and synaptic neurotransmission, form part of the blood-brain barrier, and regulate regional blood flow. Although astrocytes have been known to display morphological alterations in Alzheimer's disease for more than a century, research has remained neurocentric. Emerging evidence suggests that these morphological changes reflect functional alterations that affect disease. RECENT DEVELOPMENTS: Genetic studies indicate that most of the risk of developing late onset Alzheimer's disease, the most common form of the disease, affecting patients aged 65 years and older, is associated with genes (ie, APOE, APOJ, and SORL) that are mainly expressed by glial cells (ie, astrocytes, microglia, and oligodendrocytes). This insight has moved the focus of research away from neurons and towards glial cells and neuroinflammation. Molecular studies in rodent models suggest a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease; however, these models might insufficiently mimic the human disease, because rodent astrocytes differ considerably in morphology, functionality, and gene expression. In-vivo studies using stem-cell derived human astrocytes are allowing exploration of the human disease and providing insights into the neurotoxic or protective contributions of these cells to the pathogenesis of disease. The first attempts to develop astrocytic biomarkers and targeted therapies are emerging. WHERE NEXT?: Single-cell transcriptomics allows the fate of individual astrocytes to be followed in situ and provides the granularity needed to describe healthy and pathological cellular states at different stages of Alzheimer's disease. Given the differences between human and rodent astroglia, study of human cells in this way will be crucial. Although refined single-cell transcriptomic analyses of human post-mortem brains are important for documentation of pathology, they only provide snapshots of a dynamic reality. Thus, functional work studying human astrocytes generated from stem cells and exposed to pathological conditions in rodent brain or cell culture are needed to understand the role of these cells in the pathogenesis of Alzheimer's disease. These studies will lead to novel biomarkers and hopefully a series of new drug targets to tackle this disease

Neurodegeneration: From cellular concepts to clinical applications

Developing therapies for neurodegenerative diseases will require new scientific approaches that take into account the detrimental effects of altered protein and RNA homeostasis on brain cells, the vulnerabilities of various organelles in certain diseases and aging neurons, and the complex multicellular interactions of the nervous system

Cellular senescence at the crossroads of inflammation and Alzheimer's disease

Aging is a key risk factor for Alzheimer's disease (AD), but the reasons for this association are not well understood. Senescent cells accumulate in aged tissues and have been shown to play causal roles in age-related pathologies through their proinflammatory secretome. The question arises whether senescence-induced inflammation might contribute to AD and bridge the gap between aging and AD. Here, we highlight the role of cellular senescence as a driver of the aging phenotype, and discuss the current evidence that connects senescence with AD and neurodegeneration

Identification and in vivo characterization of a brain-penetrating nanobody

BACKGROUND: Preclinical models to determine blood to brain transport ability of therapeutics are often ambiguous. In this study a method is developed that relies on CNS target-engagement and is able to rank brain-penetrating capacities. This method led to the discovery of an anti-transferrin receptor nanobody that is able to deliver a biologically active peptide to the brain via receptor-mediated transcytosis. METHODS: Various nanobodies against the mouse transferrin receptor were fused to neurotensin and injected peripherally in mice. Neurotensin is a neuropeptide that causes hypothermia when present in the brain but is unable to reach the brain from the periphery. Continuous body temperature measurements were used as a readout for brain penetration of nanobody-neurotensin fusions after its peripheral administration. Full temperature curves were analyzed using two-way ANOVA with Dunnett multiple comparisons tests. RESULTS: One anti-transferrin receptor nanobody coupled to neurotensin elicited a drop in body temperature following intravenous injection. Epitope binning indicated that this nanobody bound a distinct transferrin receptor epitope compared to the non-crossing nanobodies. This brain-penetrating nanobody was used to characterize the in vivo hypothermia model. The hypothermic effect caused by neurotensin is dose-dependent and could be used to directly compare peripheral administration routes and various nanobodies in terms of brain exposure. CONCLUSION: This method led to the discovery of an anti-transferrin receptor nanobody that can reach the brain via receptor-mediated transcytosis after peripheral administration. This method could be used to assess novel proteins for brain-penetrating capabilities using a target-engaging readout

The promise of microRNA-based therapies in Alzheimer's disease: challenges and perspectives

Multi-pathway approaches for the treatment of complex polygenic disorders are emerging as alternatives to classical monotarget therapies and microRNAs are of particular interest in that regard. MicroRNA research has come a long way from their initial discovery to the cumulative appreciation of their regulatory potential in healthy and diseased brain. However, systematic interrogation of putative therapeutic or toxic effects of microRNAs in (models of) Alzheimer’s disease is currently missing and fundamental research findings are yet to be translated into clinical applications. Here, we review the literature to summarize the knowledge on microRNA regulation in Alzheimer’s pathophysiology and to critically discuss whether and to what extent these increasing insights can be exploited for the development of microRNA-based therapeutics in the clinic

Aducanumab: a new phase in therapeutic development for Alzheimer’s disease?

On 7 June(,) the FDA approved aducanumab, the first new drug for Alzheimer’s disease in almost 20 years—and notably, the first drug with a putative disease‐modifying mechanism for the treatment of this devastating disorder, namely the removal of β‐amyloid (or Aβ) plaques from the brain

From Junk to Function: LncRNAs in CNS Health and Disease

Recent advances in RNA sequencing technologies helped to uncover the existence of tens of thousands of long non-coding RNAs (lncRNAs) that arise from the dark matter of the genome. These lncRNAs were originally thought to be transcriptional noise but an increasing number of studies demonstrate that these transcripts can modulate protein-coding gene expression by a wide variety of transcriptional and post-transcriptional mechanisms. The spatiotemporal regulation of lncRNA expression is particularly evident in the central nervous system, suggesting that they may directly contribute to specific brain processes, including neurogenesis and cellular homeostasis. Not surprisingly, lncRNAs are therefore gaining attention as putative novel therapeutic targets for disorders of the brain. In this review, we summarize the recent insights into the functions of lncRNAs in the brain, their role in neuronal maintenance, and their potential contribution to disease. We conclude this review by postulating how these RNA molecules can be targeted for the treatment of yet incurable neurological disorders

Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Ab Peptide Seeds

Recently it was proposed that the familial Alzheimer’s disease (FAD) causing presenilin (PSEN) mutations PSEN1-L435F and PSEN1-C410Y do not support the generation of Aβ-peptides from the amyloid precursor protein (APP). This challenges the amyloid hypothesis and disagrees with previous work showing that PSEN1 FAD causing mutations generate invariably long Aβ and seed amyloid. We contrast here the proteolytic activities of these mutant PSEN alleles with the complete loss-of-function PSEN1-D257A allele. We find residual carboxy- and endo-peptidase γ-secretase activities, similar to the formerly characterized PSEN1-R278I. We conclude that the PSEN1-L435F and -C410Y mutations are extreme examples of the previously proposed “dysfunction” of γ-secretase that characterizes FAD-associated PSEN. This Matters Arising paper is in response to Xia et al. (2015), published in Neuron. See also the response by Xia et al. (2016), published in this issue