ABSTRACT
Alzheimer's disease (AD) is the most common type of dementia, accounting for 60% to 80% of all cases [...].
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/etiology , Alzheimer Disease/pathologyABSTRACT
The brain of a 58-year-old woman was included as a civilian control in an ongoing autopsy study of military traumatic brain injury (TBI). The woman died due to a polysubstance drug overdose, with Coronavirus Disease 2019 (COVID-19) serving as a contributing factor. Immunohistochemical stains for ß-amyloid (Aß), routinely performed for the TBI study, revealed numerous, unusual neocortical Aß deposits. We investigated the autopsied brains of 10 additional young patients (<60 years old) who died of COVID-19, and found similar Aß deposits in all, using two different Aß antibodies across three different medical centers. The deposits failed to stain with Thioflavin-S. To investigate whether or not these deposits formed uniquely to COVID-19, we applied Aß immunostains to the autopsied brains of COVID-19-negative adults who died with acute respiratory distress syndrome and infants with severe cardiac anomalies, and also biopsy samples from patients with subacute cerebral infarcts. Cortical Aß deposits were also found in these cases, suggesting a link to hypoxia. The fate of these deposits and their effects on function are unknown, but it is possible that they contribute to the neurocognitive sequelae observed in some COVID-19 patients. Our findings may also have broader implications concerning hypoxia and its role in Aß deposition in the brain.
Subject(s)
Alzheimer Disease , Brain Injuries, Traumatic , COVID-19 , Neocortex , Humans , Adult , Female , Middle Aged , Neocortex/pathology , COVID-19/complications , Amyloid beta-Peptides/metabolism , Brain/pathology , Brain Injuries, Traumatic/pathology , Hypoxia/pathology , Alzheimer Disease/pathologyABSTRACT
OBJECTIVE: Primary age-related tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta-amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are underappreciated. METHODS: We compare prevalence of LATE-NC and vascular copathologies in age- and Braak-matched patients with PART (n = 45, Braak stage I-IV, Thal phase 0-2) or early stage Alzheimer disease neuropathologic change (ADNC; n = 51, Braak I-IV, Thal 3-5), and examine their influence on clinical and cognitive decline. RESULTS: Concomitant LATE-NC and vascular pathology were equally common, and cognition was equally impaired, in PART (Mini-Mental State Examination [MMSE] = 24.8 ± 6.9) and ADNC (MMSE = 24.2 ± 6.0). Patients with LATE-NC were more impaired than those without LATE-NC on the MMSE (by 5.8 points, 95% confidence interval [CI] = 3.0-8.6), Mattis Dementia Rating Scale (DRS; 17.5 points, 95% CI = 7.1-27.9), Clinical Dementia Rating, sum of boxes scale (CDR-sob; 5.2 points, 95% CI = 2.1-8.2), memory composite (0.8 standard deviations [SD], 95% CI = 0.1-1.6), and language composite (1.1 SD, 95% CI = 0.2-2.0), and more likely to receive a dementia diagnosis (odds ratio = 4.8, 95% CI = 1.5-18.0). Those with vascular pathology performed worse than those without on the DRS (by 10.2 points, 95% CI = 0.1-20.3) and executive composite (1.3 SD, 95% CI = 0.3-2.3). Cognition declined similarly in PART and ADNC over the 5 years preceding death; however, LATE-NC was associated with more rapid decline on the MMSE (ß = 1.9, 95% CI = 0.9-3.0), DRS (ß = 7.8, 95% CI = 3.4-12.7), CDR-sob (ß = 1.9, 95% CI = 0.4-3.7), language composite (ß = 0.5 SD, 95% CI = 0.1-0.8), and vascular pathology with more rapid decline on the DRS (ß = 5.2, 95% CI = 0.6-10.2). INTERPRETATION: LATE-NC, and to a lesser extent vascular copathology, exacerbate cognitive impairment and decline in PART and early stage ADNC. ANN NEUROL 2022;92:425-438.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Tauopathies , Alzheimer Disease/pathology , Cognitive Dysfunction/pathology , DNA-Binding Proteins , Humans , Neurofibrillary Tangles/pathology , Plaque, Amyloid/pathology , Tauopathies/pathologyABSTRACT
PURPOSE: Cerebral amyloid angiopathy (CAA) is a common neuropathological finding and clinical entity that occurs independently and with co-existent Alzheimer's disease (AD) and small vessel disease. We compared diffusion tensor imaging (DTI) metrics of the fornix, the primary efferent tract of the hippocampus between CAA, AD and Mild Cognitive Impairment (MCI) and healthy controls. METHODS: Sixty-eight healthy controls, 32 CAA, 21 AD, and 26 MCI patients were recruited at two centers. Diffusion tensor images were acquired at 3 T with high spatial resolution and fluid-attenuated inversion recovery (FLAIR) to suppress cerebrospinal fluid (CSF) and minimize partial volume effects on the fornix. The fornix was delineated with deterministic tractography to yield mean diffusivity (MD), axial diffusivity (AXD), radial diffusivity (RD), fractional anisotropy (FA) and tract volume. Volumetric measurements of the hippocampus, thalamus, and lateral ventricles were obtained using T1-weighted MRI. RESULTS: Diffusivity (MD, AXD, and RD) of the fornix was highest in AD followed by CAA compared to controls; the MCI group was not significantly different from controls. FA was similar between groups. Fornix tract volume was â¼ 30% lower for all three patient groups compared to controls, but not significantly different between the patient groups. Thalamic and hippocampal volumes were preserved in CAA, but lower in AD and MCI compared to controls. Lateral ventricular volumes were increased in CAA, AD and MCI. Global cognition, memory, and executive function all correlated negatively with fornix diffusivity across the combined clinical group. CONCLUSION: There were significant diffusion changes of the fornix in CAA, AD and MCI compared to controls, despite relatively intact thalamic and hippocampal volumes in CAA, suggesting the mechanisms for fornix diffusion abnormalities may differ in CAA compared to AD and MCI.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Cognitive Dysfunction , Alzheimer Disease/pathology , Anisotropy , Cognitive Dysfunction/complications , Cognitive Dysfunction/diagnostic imaging , Diffusion Tensor Imaging/methods , Fornix, Brain/diagnostic imaging , Fornix, Brain/pathology , HumansABSTRACT
The early prediction of Alzheimer's disease (AD) can be vital for the endurance of patients and establishes as an accommodating and facilitative factor for specialists. The proposed work presents a robotized predictive structure, dependent on machine learning (ML) methods for the forecast of AD. Neuropsychological measures (NM) and magnetic resonance imaging (MRI) biomarkers are deduced and passed on to a recurrent neural network (RNN). In the RNN, we have used long short-term memory (LSTM), and the proposed model will predict the biomarkers (feature vectors) of patients after 6, 12, 21 18, 24, and 36 months. These predicted biomarkers will go through fully connected neural network layers. The NN layers will then predict whether these RNN-predicted biomarkers belong to an AD patient or a patient with a mild cognitive impairment (MCI). The developed methodology has been tried on an openly available informational dataset (ADNI) and accomplished an accuracy of 88.24%, which is superior to the next-best available algorithms.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Alzheimer Disease/diagnosis , Alzheimer Disease/pathology , Biomarkers , Cognitive Dysfunction/diagnostic imaging , Humans , Magnetic Resonance Imaging/methods , Memory, Short-TermABSTRACT
Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer's disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.
Subject(s)
Extracellular Vesicles/metabolism , MicroRNAs/metabolism , Nanoparticles/metabolism , Alzheimer Disease/pathology , Angiotensin-Converting Enzyme 2/metabolism , Biological Transport/physiology , Biomarkers/metabolism , COVID-19/pathology , Cardiovascular Diseases/pathology , Cell Communication/physiology , Cell Line, Tumor , HeLa Cells , Humans , Lactic Acid/metabolism , MicroRNAs/genetics , Nanoparticles/classification , Neoplasms/pathology , Tumor MicroenvironmentSubject(s)
2',5'-Oligoadenylate Synthetase/genetics , Anosmia/etiology , COVID-19/pathology , Spike Glycoprotein, Coronavirus/genetics , Alleles , Alzheimer Disease/genetics , Alzheimer Disease/pathology , COVID-19/complications , COVID-19/virology , Genome-Wide Association Study , Humans , Olfactory Bulb/metabolism , Polymorphism, Genetic , Prognosis , Risk Factors , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Severity of Illness IndexABSTRACT
Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer's disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.
Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/virology , Brain/pathology , Brain/virology , Endogenous Retroviruses/pathogenicity , Virus Diseases/pathology , Virus Diseases/virology , Animals , Cognition Disorders/pathology , Cognition Disorders/virology , Encephalitis/pathology , Encephalitis/virology , HumansABSTRACT
Among millions of sufferers of chronic rhinosinusitis (CRS), the challenge is not only constantly coping with CRS-related symptoms, such as congested nose, sinus pain, and headaches, but also various complications, such as attention difficulties and possible depression. These complications suggest that neural activity in the central nervous system may be altered in those patients, leading to unexpected conditions, such as neurodegeneration in elderly patients. Recently, some studies linked the presence of CRS and cognitive impairments that could further develop into Alzheimer's disease (AD). AD is the leading cause of dementia in the elderly and is characterised by progressive memory loss, cognitive behavioural deficits, and significant personality changes. The microbiome, especially those in the gut, has been recognised as a human organ and plays an important role in the development of various conditions, including AD. However, less attention has been paid to the microbiome in the nasal cavity. Increased nasal inflammatory responses due to CRS may be an initial event that changes local microbiome homeostasis, which may further affect neuronal integrity in the central nervous system resulting in AD. Evidence suggests a potential of ß-amyloid deposition starting in olfactory neurons, which is then expanded from the nasal cavity to the central nervous system. In this paper, we reviewed currently available evidence that suggests this potential mechanism to advise the need to investigate the link between these two conditions.
Subject(s)
Alzheimer Disease/microbiology , Nose/microbiology , Rhinitis/complications , Sinusitis/complications , Alzheimer Disease/etiology , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Brain/pathology , Chronic Disease , Humans , Microbiota , Rhinitis/microbiology , Rhinitis/pathology , Sinusitis/microbiology , Sinusitis/pathologyABSTRACT
γ-secretase is a macromolecular complex that catalyzes intramembranous hydrolysis of more than 100 membrane-bound substrates. The complex is composed of presenilin (PS1 or PS2), anterior pharynx defect-1 (APH-1), nicastrin (NCT) and PEN-2 and early-onset; autosomal dominant forms of Alzheimer's disease (AD) are caused by inheritance of mutations of PS. No mutations in genes encoding NCT, or PEN-2 have been identified to date that cause AD. In this regard, a large genetic meta-analysis of four cohorts consisting of more than 600 000 individuals identified a common missense variant, rs117618017 in the APH1B gene that results in a T27I mutation, as a novel genome-wide significant locus. In order to confirm the findings that rs117618017 is associated with risk of AD, we performed a genetic screen from deep whole genome sequencing of the large NIMH family-based Alzheimer's Disease (AD) dataset. In parallel, we sought to uncover potential molecular mechanism(s) by which APH-1B T27I might be associated with AD by generating stable HEK293 cell lines, wherein endogenous APH-1A and APH-1B expression was silenced and into which either the wild type APH-1B or the APH-1B T27I variant was stably expressed. We then tested the impact of expressing either the wild type APH-1B or the APH-1B T27I variant on γ-secretase processing of human APP, the murine Notch derivative mNΔE and human neuregulin-1. We now report that we fail to confirm the association of rs1047552 with AD in our cohort and that cells expressing the APH-1B T27I variant show no discernable impact on the γ-secretase processing of established substrates compared with cells expressing wild-type APH-1B.
Subject(s)
Alzheimer Disease/pathology , Amyloid Precursor Protein Secretases/metabolism , Endopeptidases/genetics , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , Alzheimer Disease/genetics , HEK293 Cells , Humans , Mutation , Protein BindingABSTRACT
Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer's disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.
Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Alzheimer Disease/metabolism , Animals , Coronavirus/pathogenicity , Humans , Immunity, Innate , Microglia/metabolism , Virus Diseases/immunology , Virus Diseases/pathologyABSTRACT
As mitochondria network together to act as the master sensors and effectors of apoptosis, ATP production, reactive oxygen species management, mitophagy/autophagy, and homeostasis; this organelle is an ideal target for pharmaceutical manipulation. Mitochondrial dysfunction contributes to many diseases, for example, ß-amyloid has been shown to interfere with mitochondrial protein import and induce apoptosis in Alzheimer's Disease while some forms of Parkinson's Disease are associated with dysfunctional mitochondrial PINK1 and Parkin proteins. Mitochondrial medicine has applications in the treatment of an array of pathologies from cancer to cardiovascular disease. A challenge of mitochondrial medicine is directing therapies to a subcellular target. Nanotechnology based approaches combined with mitochondrial targeting strategies can greatly improve the clinical translation and effectiveness of mitochondrial medicine. This review discusses mitochondrial drug delivery approaches and applications of mitochondrial nanomedicines. Nanomedicine approaches have the potential to drive the success of mitochondrial therapies into the clinic.
Subject(s)
Alzheimer Disease/drug therapy , Mitochondria/drug effects , Nanomedicine , Parkinson Disease/drug therapy , Adenosine Triphosphate/biosynthesis , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Autophagy/drug effects , Autophagy/genetics , Humans , Mitochondria/genetics , Mitophagy/drug effects , Mitophagy/genetics , Parkinson Disease/genetics , Parkinson Disease/pathology , Reactive Oxygen SpeciesABSTRACT
Alzheimer's disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of patients with Alzheimer's disease. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer's disease and ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease, and brains with the disease examined in this study also exhibited higher carbonylated proteins, as well as an increased thiol oxidation state of peroxiredoxin 6 (Prx6). A moderate positive correlation was found between the increased ACE2 protein expression and oxidative stress in brains with Alzheimer's disease. In summary, the present study reveals the relationships between Alzheimer's disease and ACE2, the receptor for SARS-CoV-2. These results suggest the importance of carefully monitoring patients with both Alzheimer's disease and COVID-19 in order to identify higher viral loads in the brain and long-term adverse neurological consequences.
Subject(s)
Alzheimer Disease/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , COVID-19/metabolism , Hippocampus/metabolism , Pandemics , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Up-Regulation , Alzheimer Disease/complications , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Autopsy , COVID-19/complications , COVID-19/virology , Hippocampus/pathology , Humans , Oxidation-Reduction , Oxidative Stress , Peroxiredoxin VI/metabolism , Plaque, Amyloid/metabolism , Protein Carbonylation , Severity of Illness Index , Virus InternalizationABSTRACT
Neprilysin (NEP) is an integral membrane-bound metallopeptidase with a wide spectrum of substrates and physiological functions. It plays an important role in proteolytic processes in the kidney, cardiovascular regulation, immune response, cell proliferation, foetal development etc. It is an important neuropeptidase and amyloid-degrading enzyme which makes NEP a therapeutic target in Alzheimer's disease (AD). Moreover, it plays a preventive role in development of cancer, obesity and type-2 diabetes. Recently a role of NEP in COVID-19 pathogenesis has also been suggested. Despite intensive research into NEP structure and functions in different organisms, changes in its expression and regulation during brain development and ageing, especially in age-related pathologies, is still not fully understood. This prevents development of pharmacological treatments from various diseases in which NEP is implicated although recently a dual-acting drug sacubitril-valsartan (LCZ696) combining a NEP inhibitor and angiotensin receptor blocker has been approved for treatment of heart failure. Also, various natural compounds capable of upregulating NEP expression, including green tea (EGCG), have been proposed as a preventive medicine in prostate cancer and AD. This review summarizes the existing literature and our own research on the expression and activity of NEP in normal brain development, ageing and under pathological conditions.
Subject(s)
Aging/immunology , Alzheimer Disease/immunology , COVID-19/immunology , Diabetes Mellitus, Type 2/immunology , Gene Expression Regulation, Enzymologic/immunology , Gene Expression Regulation, Neoplastic/immunology , Neoplasm Proteins/immunology , Neoplasms/immunology , Neprilysin/immunology , SARS-CoV-2/immunology , Aging/pathology , Alzheimer Disease/pathology , Animals , COVID-19/pathology , Diabetes Mellitus, Type 2/pathology , Humans , Neoplasms/pathologyABSTRACT
The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1ß, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer's disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4'-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen's disease, also diagnosed as Alzheimer's disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson's disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.