Microglia Heterogeneity in Alzheimer’s Disease: Insights From Single-Cell Technologies

Microglia are resident immune cells in the central nervous system and play critical roles in brain immunity, development, and homeostasis. The pathology of Alzheimer’s disease (AD) triggers activation of microglia. Microglia express many AD risk genes, suggesting that their response to AD pathology can affect disease progression. Microglia have long been considered a homogenous cell population. The diversity of microglia has gained great interest in recent years due to the emergence of novel single-cell technologies, such as single-cell/nucleus RNA sequencing and single-cell mass cytometry by time-of-flight. This review summarizes the current knowledge about the diversity/heterogeneity of microglia and distinct microglia states in the brain of both AD mouse models and patients, as revealed by single-cell technologies. It also discusses the future developments for application of single-cell technologies and the integration of these technologies with functional studies to further dissect microglia biology in AD. Defining the functional correlates of distinct microglia states will shed new light on the pathological roles of microglia and might uncover new relevant therapeutic targets for AD.

Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21228767 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8767

Author(s):

Nicole Jacqueline Jensen ◽

Helena Zander Wodschow ◽

Malin Nilsson ◽

Jørgen Rungby

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Brain Metabolism ◽

Ketone Bodies ◽

Current Knowledge ◽

Ketogenic Diets ◽

Cognitive Benefits ◽

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

The Presence of Human Herpesvirus 6 in the Brain in Health and Disease

Biomolecules ◽

10.3390/biom10111520 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1520

Author(s):

Gabriel Santpere ◽

Marco Telford ◽

Pol Andrés-Benito ◽

Arcadi Navarro ◽

Isidre Ferrer

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Current Knowledge ◽

Human Herpesvirus ◽

Brain Regions ◽

Specific Cell ◽

Human Herpesvirus 6 ◽

Detection Techniques ◽

Herpesvirus 6 ◽

The human herpesvirus 6 (HHV‐6) ‐A and ‐B are two dsDNA beta‐herpesviruses infectingalmost the entire worldwide population. These viruses have been implicated in multipleneurological conditions in individuals of various ages and immunological status, includingencephalitis, epilepsy, and febrile seizures. HHV‐6s have also been suggested as playing a role inthe etiology of neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease. Theapparent robustness of these suggested associations is contingent on the accuracy of HHV‐6detection in the nervous system. The effort of more than three decades of researching HHV‐6 in thebrain has yielded numerous observations, albeit using variable technical approaches in terms oftissue preservation, detection techniques, sample sizes, brain regions, and comorbidities. In thisreview, we aimed to summarize current knowledge about the entry routes and direct presence ofHHV‐6 in the brain parenchyma at the level of DNA, RNA, proteins, and specific cell types, inhealthy subjects and in those with neurological conditions. We also discuss recent findings relatedto the presence of HHV‐6 in the brains of patients with Alzheimer’s disease in light of availableevidence.

The relationship of diabetes mellitus with Alzheimer’s disease: a literature review

10.5327/1516-3180.280 ◽

2021 ◽

Author(s):

Fábio Dias Nogueira ◽

Ana Klara Rodrigues Alves ◽

Barbara Beatriz Lira da Silva ◽

Ana Kamila Rodrigues Alves ◽

Marlilia Moura Coelho Sousa ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Potential Link ◽

Gsk 3Β ◽

Type 3 ◽

Introduction: Alzheimer’s disease (AD) is closely related to diabetes mellitus (DM), and AD is also considered to be type 3 diabetes (T3D). Glycogen synthase kinase-3β (GSK-3β) may be the potential link between DM and AD. GSK-3β is one of the main factors that lead to insulin deficiency and insulin resistance, and insulin resistance is a characteristic of the development of DM. In AD, GSK-3β plays an important role in hyperphosphorylation of the tau protein (tau) associated with microtubules, which is one of the pathological features in AD. Objective: To analyze DM as a factor for the development of AD. METHODOLOGY: This is an integrative review of the literature, which is a construction of a comprehensive analysis of the literature with pre-defined steps, carried out through PubMed, 1.501 articles were found, of which 10 were selected, through the simultaneous crossing between the descriptors “Diabetes mellitus”, “Alzheimer “. Articles written in Portuguese and English published between 2016 and 2021 were inserted. Results: DM associated with insulin resistance affects psychomotor efficiency, attention, learning memory, mental flexibility, speed and executive function of the brain, thus being an independent risk factor for cognitive impairment and damage to the central nervous system, hyperglycemia, which can cause increased oxidative stress leading to progressive functional and structural abnormalities in the brain. Conclusion:The risk of dementia in patients with DM is higher than in nondiabetic patients and it is also well known that DM2 / insulin resistance is involved in AD.

Alzheimer’s disease: many failed trials, so where do we go from here?

Journal of Investigative Medicine ◽

10.1136/jim-2020-001297 ◽

2020 ◽

Vol 68 (6) ◽

pp. 1135-1140 ◽

Cited By ~ 1

Author(s):

Allison Bethanne Reiss ◽

Amy D Glass ◽

Thomas Wisniewski ◽

Benjamin Wolozin ◽

Irving H Gomolin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Current Knowledge ◽

Memory Loss ◽

Treatment Strategies ◽

Amyloid Β ◽

Tau Proteins ◽

Brain Disorder ◽

Progressive Cognitive Impairment

Alzheimer’s disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive cognitive impairment and memory loss. AD pathology proceeds for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy. Imbalance of clearance and buildup of amyloid β and phosphorylated tau proteins in the central nervous system is believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success, and there is still no disease-modifying intervention. Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.690372 ◽

2021 ◽

Vol 13 ◽

Author(s):

Femke M. Feringa ◽

Rik van der Kant

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholesterol Metabolism ◽

Late Onset ◽

Induced Pluripotent Stem Cell ◽

Risk Genes ◽

Cholesterol Levels ◽

Technical Advances ◽

Induced Pluripotent

While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body’s cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer’s disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer’s disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems.

Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21010209 ◽

2019 ◽

Vol 21 (1) ◽

pp. 209 ◽

Cited By ~ 3

Author(s):

Tao Zhang ◽

Dongmei Chen ◽

Tae Ho Lee

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathways ◽

Physiological Function ◽

Amyloid Β ◽

Proteolytic Processing ◽

App Processing ◽

Abnormal Accumulation ◽

The abnormal accumulation of amyloid-β (Aβ) in the central nervous system is a hallmark of Alzheimer’s disease (AD). The regulation of the processing of the single- transmembrane amyloid precursor protein (APP) plays an important role in the generation of Aβ in the brain. The phosphorylation of APP and key enzymes involved in the proteolytic processing of APP has been demonstrated to be critical for modulating the generation of Aβ by either altering the subcellular localization of APP or changing the enzymatic activities of the secretases responsible for APP processing. In addition, the phosphorylation may also have an impact on the physiological function of these proteins. In this review, we summarize the kinases and signaling pathways that may participate in regulating the phosphorylation of APP and secretases and how this further affects the function and processing of APP and Aβ pathology. We also discuss the potential of approaches that modulate these phosphorylation-signaling pathways or kinases as interventions for AD pathology.

Biomarkers for Alzheimer’s Disease Early Diagnosis

Journal of Personalized Medicine ◽

10.3390/jpm10030114 ◽

2020 ◽

Vol 10 (3) ◽

pp. 114 ◽

Cited By ~ 2

Author(s):

Eva Ausó ◽

Violeta Gómez-Vicente ◽

Gema Esquiva

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Loss ◽

Diagnostic Tools ◽

Csf Biomarkers ◽

Diagnosis And Prognosis ◽

Positron Emission ◽

Magnetic Resonance Imaging Mri ◽

Alzheimer’s disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain and retinal regions. Therefore, the availability of early and reliable diagnosis markers of the disease would allow its detection and taking preventive measures to avoid neuronal loss. Current diagnostic tools in the brain, such as magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and cerebrospinal fluid (CSF) biomarkers (Aβ and tau) detection are invasive and expensive. Brain-secreted extracellular vesicles (BEVs) isolated from peripheral blood have emerged as novel strategies in the study of AD, with enormous potential as a diagnostic evaluation of therapeutics and treatment tools. In addition; similar mechanisms of neurodegeneration have been demonstrated in the brain and the eyes of AD patients. Since the eyes are more accessible than the brain, several eye tests that detect cellular and vascular changes in the retina have also been proposed as potential screening biomarkers. The aim of this study is to summarize and discuss several potential markers in the brain, eye, blood, and other accessible biofluids like saliva and urine, and correlate them with earlier diagnosis and prognosis to identify individuals with mild symptoms prior to dementia.

Retinoic Acid and the Gut Microbiota in Alzheimer’s Disease: Fighting Back-to-Back?

Current Alzheimer Research ◽

10.2174/1567205016666190321163705 ◽

2019 ◽

Vol 16 (5) ◽

pp. 405-417 ◽

Cited By ~ 4

Author(s):

Kristina Endres

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Retinoic Acid ◽

Gut Microbiota ◽

Disease Risk ◽

Current Knowledge ◽

Retinoid Signaling ◽

Retinoid Metabolism ◽

Organ Systems ◽

Background: There is growing evidence that the gut microbiota may play an important role in neurodegenerative diseases such as Alzheimer’s disease. However, how these commensals influence disease risk and progression still has to be deciphered. Objective: The objective of this review was to summarize current knowledge on the interplay between gut microbiota and retinoic acid. The latter one represents one of the important micronutrients, which have been correlated to Alzheimer’s disease and are used in initial therapeutic intervention studies. Methods: A selective overview of the literature is given with the focus on the function of retinoic acid in the healthy and diseased brain, its metabolism in the gut, and the potential influence that the bioactive ligand may have on microbiota, gut physiology and, Alzheimer’s disease. Results: Retinoic acid can influence neuronal functionality by means of plasticity but also by neurogenesis and modulating proteostasis. Impaired retinoid-signaling, therefore, might contribute to the development of diseases in the brain. Despite its rather direct impact, retinoic acid also influences other organ systems such as gut by regulating the residing immune cells but also factors such as permeability or commensal microbiota. These in turn can also interfere with retinoid-metabolism and via the gutbrain- axis furthermore with Alzheimer’s disease pathology within the brain. Conclusion: Potentially, it is yet too early to conclude from the few reports on changed microbiota in Alzheimer’s disease to a dysfunctional role in retinoid-signaling. However, there are several routes how microbial commensals might affect and might be affected by vitamin A and its derivatives.

Brothers in arms: proBDNF/BDNF and sAPPα/Aβ-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of Alzheimer’s disease

Biological Chemistry ◽

10.1515/hsz-2021-0330 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Simone Eggert ◽

Stefan Kins ◽

Kristina Endres ◽

Tanja Brigadski

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Death ◽

Common Features ◽

Interaction Partners ◽

Bdnf Signaling ◽

The Common ◽

Abstract Brain-derived neurotrophic factor (BDNF) is an important modulator for a variety of functions in the central nervous system (CNS). A wealth of evidence, such as reduced mRNA and protein level in the brain, cerebrospinal fluid (CSF), and blood samples of Alzheimer’s disease (AD) patients implicates a crucial role of BDNF in the progression of this disease. Especially, processing and subcellular localization of BDNF and its receptors TrkB and p75 are critical determinants for survival and death in neuronal cells. Similarly, the amyloid precursor protein (APP), a key player in Alzheimer’s disease, and its cleavage fragments sAPPα and Aβ are known for their respective roles in neuroprotection and neuronal death. Common features of APP- and BDNF-signaling indicate a causal relationship in their mode of action. However, the interconnections of APP- and BDNF-signaling are not well understood. Therefore, we here discuss dimerization properties, localization, processing by α- and γ-secretase, relevance of the common interaction partners TrkB, p75, sorLA, and sortilin as well as shared signaling pathways of BDNF and sAPPα.