scholarly journals The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

2020 ◽  
Vol 140 (4) ◽  
pp. 417-447 ◽  
Author(s):  
Sarah A. Kent ◽  
Tara L. Spires-Jones ◽  
Claire S. Durrant
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Metabolism ◽  
Learning And Memory ◽  
Iron Homeostasis ◽  
Neuronal Excitability ◽  
Biological Processes ◽  
Dna Protection ◽  
Function Learning ◽  
Therapeutic Development

Abstract Tau and amyloid beta (Aβ) are the prime suspects for driving pathology in Alzheimer’s disease (AD) and, as such, have become the focus of therapeutic development. Recent research, however, shows that these proteins have been highly conserved throughout evolution and may have crucial, physiological roles. Such functions may be lost during AD progression or be unintentionally disrupted by tau- or Aβ-targeting therapies. Tau has been revealed to be more than a simple stabiliser of microtubules, reported to play a role in a range of biological processes including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning and memory, neuronal excitability, and DNA protection. Aβ is similarly multifunctional, and is proposed to regulate learning and memory, angiogenesis, neurogenesis, repair leaks in the blood–brain barrier, promote recovery from injury, and act as an antimicrobial peptide and tumour suppressor. This review will discuss potential physiological roles of tau and Aβ, highlighting how changes to these functions may contribute to pathology, as well as the implications for therapeutic development. We propose that a balanced consideration of both the physiological and pathological roles of tau and Aβ will be essential for the design of safe and effective therapeutics.

Mitochondria in Neuroplasticity, Neurologic Disease and Aging.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-2-SCI-2 ◽  
Author(s):  
Mark P. Mattson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bone Marrow ◽  
Learning And Memory ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Receptor Expression ◽  
Health And Disease ◽  
Energy Deprivation ◽  
The Brain

Abstract Abstract SCI-2 Brain cells are influenced in health and disease by several types of bone marrow-derived cells (BMDC) that either reside in, or are recruited to, the brain. Microglia are macrophage-like cells that continuously surveil the brain, and respond to injury, infection or disease by endocytosing damaged/dead cells and microorganisms, and by producing pro-inflammatory cytokines. Lymphocytes of various phenotypes enter the brain in large numbers in response to acute injury (stroke, severe epileptic seizures, trauma) or chronic disease (multiple sclerosis, Alzheimer's disease). While microglia and lymphocytes are best known for their adverse effects on neuronal function and survival in injury or disease (Arumugam et al., Nat Med. 2006; 12:621-3), recent findings suggest that these cells may also serve important beneficial roles in processes such as learning and memory (Ziv et al. Nat Neurosci. 2006; 9:268-75). Here I describe how BMDC can affect neuronal excitability and mitochondrial function in normal physiological settings and in disease states. We have found that low concentrations of tumor necrosis factor (TNF), which is produced by microglia/macrophages and lymphocytes, can promote neuronal survival and synaptic plasticity by activating the transcription factor NF-kB to induce the expression of glutamate receptor subunits, mitochondrial SOD2 and Bcl2 (Mattson and Meffert, Cell Death Differ. 2006; 13:852-60). When bone marrow from TNF receptor-deficient mice was transplanted into irradiated wild type mice, neurons in the brain were more vulnerable to epileptic seizures, suggesting that TNF suppresses neuronal excitability (Guo et al., Neuromolecular Med. 2004; 5:219-34). In other studies we found that a mutation in presenilin-1 (PS1) that causes early-onset inherited Alzheimer's disease (AD) perturbs lymphocyte signaling (Morgan et al., Neuromolecular Med. 2007; 9:35-45). Splenic T cells isolated from PS1 mutant knockin mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. The adverse effect of mutant PS1 involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to mitochondria-mediated apoptosis. These findings suggest that abnormalities in immune function might play roles in the pathogenesis of AD. Finally, I describe very recent findings that suggest roles for toll-like receptor signaling in learning and memory processes, and in neuronal responses to energy deprivation (Tang et al., Proc Natl Acad Sci U S A. 2007; 104:13798-803). Emerging findings therefore suggest that both innate and humoral signaling from BMDC to neurons play interesting roles in regulating neuronal plasticity and energy metabolism in health and disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Topographic patterns of white matter hyperintensities are associated with multimodal neuroimaging biomarkers of Alzheimer’s disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Malo Gaubert ◽  
Catharina Lange ◽  
Antoine Garnier-Crussard ◽  
Theresa Köbe ◽  
Salma Bougacha ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Glucose Metabolism ◽  
Corpus Callosum ◽  
Gray Matter ◽  
Fdg Pet ◽  
White Matter Hyperintensities ◽  
Gray Matter Volume ◽  
Matter Volume

Abstract Background White matter hyperintensities (WMH) are frequently found in Alzheimer’s disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (Aβ) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with Aβ burden, glucose hypometabolism, and gray matter volume reduction. Methods In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical Aβ deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure. Results There were no significant associations between global Aβ burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater Aβ deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas. Conclusions This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Aß deposition and neurodegeneration.

scholarly journals Dysregulation of Astrocyte–Neuronal Communication in Alzheimer’s Disease

2021 ◽  
Vol 22 (15) ◽  
pp. 7887
Author(s):  
Carmen Nanclares ◽  
Andres Mateo Baraibar ◽  
Alfonso Araque ◽  
Paulo Kofuji
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Neuronal Excitability ◽  
Active Role ◽  
Ionic Homeostasis ◽  
Neuronal Communication ◽  
Structural Support

Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this “active” role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD.

scholarly journals Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

2021 ◽  
Author(s):  
Wen-Dai Bao ◽  
Pei Pang ◽  
Xiao-Ting Zhou ◽  
Fan Hu ◽  
Wan Xiong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Impairment ◽  
Iron Homeostasis ◽  
Critical Role ◽  
Gene Set Enrichment Analysis ◽  
Molecular Characteristics ◽  
Intracellular Iron

AbstractIron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

scholarly journals Transcriptome analyses of 7-day-old zebrafish larvae possessing a familial Alzheimer’s disease-like mutation in psen1 indicate effects on oxidative phosphorylation, ECM and MCM functions, and iron homeostasis

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yang Dong ◽  
Morgan Newman ◽  
Stephen M. Pederson ◽  
Karissa Barthelson ◽  
Nhi Hin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Phosphorylation ◽  
Transcriptome Analysis ◽  
Iron Homeostasis ◽  
Late Onset ◽  
Wild Type ◽  
Familial Alzheimer’S Disease ◽  
Zebrafish Larvae ◽  
Familial Alzheimer's Disease

Abstract Background Early-onset familial Alzheimer’s disease (EOfAD) is promoted by dominant mutations, enabling the study of Alzheimer’s disease (AD) pathogenic mechanisms through generation of EOfAD-like mutations in animal models. In a previous study, we generated an EOfAD-like mutation, psen1Q96_K97del, in zebrafish and performed transcriptome analysis comparing entire brains from 6-month-old wild type and heterozygous mutant fish. We identified predicted effects on mitochondrial function and endolysosomal acidification. Here we aimed to determine whether similar effects occur in 7 day post fertilization (dpf) zebrafish larvae that might be exploited in screening of chemical libraries to find ameliorative drugs. Results We generated clutches of wild type and heterozygous psen1Q96_K97del 7 dpf larvae using a paired-mating strategy to reduce extraneous genetic variation before performing a comparative transcriptome analysis. We identified 228 differentially expressed genes and performed various bioinformatics analyses to predict cellular functions. Conclusions Our analyses predicted a significant effect on oxidative phosphorylation, consistent with our earlier observations of predicted effects on ATP synthesis in adult heterozygous psen1Q96_K97del brains. The dysregulation of minichromosome maintenance protein complex (MCM) genes strongly contributed to predicted effects on DNA replication and the cell cycle and may explain earlier observations of genome instability due to PSEN1 mutation. The upregulation of crystallin gene expression may be a response to defective activity of mutant Psen1 protein in endolysosomal acidification. Genes related to extracellular matrix (ECM) were downregulated, consistent with previous studies of EOfAD mutant iPSC neurons and postmortem late onset AD brains. Also, changes in expression of genes controlling iron ion transport were observed without identifiable changes in the prevalence of transcripts containing iron responsive elements (IREs) in their 3′ untranslated regions (UTRs). These changes may, therefore, predispose to the apparent iron dyshomeostasis previously observed in 6-month-old heterozygous psen1Q96_K97del EOfAD-like mutant brains.

Decreased Glucose Metabolism and Glutamine Synthesis in the Retina of a Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Author(s):  
Anna Luna Mølgaard Tams ◽  
Berta Sanz-Morello ◽  
Emil Winther Westi ◽  
Zaynab Ahmad Mouhammad ◽  
Jens Velde Andersen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Metabolism ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Model Of Alzheimer’S Disease ◽  
Glutamine Synthesis

scholarly journals Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease

2021 ◽  
Author(s):  
Shun-Fat Lau ◽  
Amy K. Y. Fu ◽  
Nancy Y. Ip
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
State Transition ◽  
Cytokine Signaling ◽  
Interleukin 33 ◽  
Beneficial Effects ◽  
Activated State ◽  
Therapeutic Development ◽  
Functional States

AbstractGenetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer’s disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome–IL-1β, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development.

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