Is amyloid involved in acute neuroinflammation? A CSF analysis in encephalitis.

INTRODUCTION: Several investigations have argued for a strong relationship between neuroinflammation and amyloid metabolism but it is still unclear whether inflammation exerts a pro-amyloidogenic effect, amplifies the neurotoxic effect of amyloid, or is protective. METHODS: Forty-two patients with acute encephalitis (ENC) and 18 controls underwent an extended cerebrospinal fluid (CSF) panel of inflammatory, amyloid (Aß40, 42, and 38, sAPP-α, sAPP-ß), glial, and neuronal biomarkers. Linear and non-linear correlations between CSF biomarkers were evaluated studying conditional independence relationships. RESULTS: CSF levels of inflammatory cytokines and neuronal/glial markers were higher in ENC compared to controls, whereas the levels of amyloid-related markers did not differ. Inflammatory markers were not associated with amyloid markers but exhibited a correlation with glial and neuronal markers in conditional independence analysis. DISCUSSION: By an extensive CSF biomarkers analysis, this study showed that an acute neuroinflammation state, which is associated with glial activation and neuronal damage, does not influence amyloid homeostasis.

Amyloid peptides with antimicrobial and/or microbial agglutination activity.

Microbe (including bacteria, fungi, and virus) infection in brains is associated with amyloid fibril deposit and neurodegeneration. Increasing findings suggest that amyloid proteins, like Abeta (Aß), are important innate immune effectors in preventing infections. In some previous studies, amyloid peptides have been linked to antimicrobial peptides due to their common mechanisms in membrane-disruption ability, while the other mechanisms of bactericidal protein aggregation and protein function knockdown are less discussed. Besides, another important function of amyloid peptides in pathogen agglutination is rarely illustrated. In this review, we summarized and divided the different roles and mechanisms of amyloid peptides against microbes in antimicrobial activity and microbe agglutination activity. Besides, the range of amyloids' antimicrobial spectrum, the effectiveness of amyloid peptide states (monomers, oligomers, and fibrils), and cytotoxicity are discussed. The good properties of amyloid peptides against microbes might provide implications for the development of novel antimicrobial drug. KEY POINTS: • Antimicrobial and/or microbial agglutination is a characteristic of amyloid peptides. • Various mechanisms of amyloid peptides against microbes are discovered recently. • Amyloid peptides might be developed into novel antimicrobial drugs.

Aß Deposits in the Neocortex of Adult and Infant Hypoxic Brains, Including in Cases of COVID-19.

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.

Prepandemic Alzheimer Disease Biomarkers and Anxious-Depressive Symptoms During the COVID-19 Confinement in Cognitively Unimpaired Adults.

BACKGROUND AND OBJECTIVES: Increased anxious-depressive symptomatology is observed in the preclinical stage of Alzheimer disease (AD), which may accelerate disease progression. We investigated whether ß-amyloid, cortical thickness in medial temporal lobe structures, neuroinflammation, and sociodemographic factors were associated with greater anxious-depressive symptoms during the COVID-19 confinement. METHODS: This retrospective observational study included cognitively unimpaired older adults from the Alzheimer's and Families cohort, the majority with a family history of sporadic AD. Participants performed the Hospital Anxiety and Depression Scale (HADS) during the COVID-19 confinement. A subset had available retrospective (on average: 2.4 years before) HADS assessment, amyloid [18F] flutemetamol PET and structural MRI scans, and CSF markers of neuroinflammation (interleukin-6 [IL-6], triggering receptor expressed on myeloid cells 2, and glial fibrillary acidic protein levels). We performed multivariable linear regression models to investigate the associations of prepandemic AD-related biomarkers and sociodemographic factors with HADS scores during the confinement. We further performed an analysis of covariance to adjust by participants' prepandemic anxiety-depression levels. Finally, we explored the role of stress and lifestyle changes (sleep patterns, eating, drinking, smoking habits, and medication use) on the tested associations and performed sex-stratified analyses. RESULTS: We included 921 (254 with AD biomarkers) participants. ß-amyloid positivity (B = 3.73; 95% CI = 1.1 to 6.36; p = 0.006), caregiving (B = 1.37; 95% CI 0.24-2.5; p = 0.018), sex (women: B = 1.95; 95% CI 1.1-2.79; p < 0.001), younger age (B = -0.12; 95% CI -0.18 to -0.052; p < 0.001), and lower education (B = -0.16; 95% CI -0.28 to -0.042; p = 0.008) were associated with greater anxious-depressive symptoms during the confinement. Considering prepandemic anxiety-depression levels, we further observed an association between lower levels of CSF IL-6 (B = -5.11; 95% CI -10.1 to -0.13; p = 0.044) and greater HADS scores. The results were independent of stress-related variables and lifestyle changes. Stratified analysis revealed that the associations were mainly driven by women. DISCUSSION: Our results link AD-related pathophysiology and neuroinflammation with greater anxious-depressive symptomatology during the COVID-19-related confinement, notably in women. AD pathophysiology may increase neuropsychiatric symptomatology in response to stressors. This association may imply a worse clinical prognosis in people at risk for AD after the pandemic and thus deserves to be considered by clinicians. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT02485730.

Insights for Alzheimer's disease pharmacotherapy and current clinical trials.

Over the years, the scientific community has sought improvements in the life quality of patients diagnosed with Alzheimer's disease (AD). Synaptic loss and neuronal death observed in the regions responsible for cognitive functions represent an irreversible progressive disease that is clinically characterized by impaired cognitive and functional abilities, along with behavioral symptoms. Currently, image and body fluid biomarkers can provide early dementia diagnostic, being it the best way to slow the disease's progression. The first signs of AD development are still complex, the existence of individual genetic and phenotypic characteristics about the disease makes it difficult to standardize studies on the subject. The answer seems to be related between Aß and tau proteins. Aß deposition in the medial parietal cortex appears to be the initial stage of AD, but it does not have a strong correlation with neurodegeneration. The strongest link between symptoms occurs with tau aggregation, which antecede Aß deposits in the medial temporal lobe, however, the protein can be found in cognitively healthy older people. The answer to the question may lie in some catalytic effect between both proteins. Amid so many doubts, Aducanumab was approved, which raised controversies and results intense debate in the scientific field. Abnormal singling of some blood biomarkers produced by adipocytes under high lipogenesis, such as TNFα, leptin, and interleukin-6, demonstrate to be linked to neuroinflammation worsens, diabetes, and also severe cases of COVID-19, howsoever, under higher lipolysis, seem to have therapeutic anti-inflammatory effects in the brain, which has increasingly contributed to the understanding of AD. In addition, the relationship of severe clinical complications caused by Sars-CoV-2 viral infection and AD, go beyond the term "risk group" and may be related to the development of dementia long-term. Thus, this review summarized the current emerging pharmacotherapies, alternative treatments, and nanotechnology applied in clinical trials, discussing relevant points that may contribute to a more accurate look.

Amyloid-beta-related angiitis: a treatable rapidly progressive dementia.

A 73-year-old woman developed cognitive decline over 1 year. MR scan of the brain showed a focal asymmetrical leukoencephalopathy involving the right frontal, temporal, parietal and occipital lobes. Extensive laboratory investigations found no cause but brain biopsy identified amyloid-beta-related angiitis (ABRA), a potentially treatable cause of rapid-onset dementia. We gave intravenous methylprednisolone and then two courses of intravenous cyclophosphamide, after which her cognitive skills gradually but significantly improved over several months.

Amyloid processing in COVID-19-associated neurological syndromes.

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1ß, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPß (p = 0.03) as well as amyloid ß (Aß) 40 (p = 5.2 × 10-8 ), Aß42 (p = 3.5 × 10-7 ), and Aß42/Aß40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPß. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPß. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPß. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.

SARS-CoV-2 Exacerbates Beta-Amyloid Neurotoxicity, Inflammation and Oxidative Stress in Alzheimer's Disease Patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the pandemic Coronavirus Disease 19 (COVID-19), causing millions of deaths. The elderly and those already living with comorbidity are likely to die after SARS-CoV-2 infection. People suffering from Alzheimer's disease (AD) have a higher risk of becoming infected, because they cannot easily follow health roles. Additionally, those suffering from dementia have a 40% higher risk of dying from COVID-19. Herein, we collected from Gene Expression Omnibus repository the brain samples of AD patients who died of COVID-19 (AD+COVID-19), AD without COVID-19 (AD), COVID-19 without AD (COVID-19) and control individuals. We inspected the transcriptomic and interactomic profiles by comparing the COVID-19 cohort against the control cohort and the AD cohort against the AD+COVID-19 cohort. SARS-CoV-2 in patients without AD mainly activated processes related to immune response and cell cycle. Conversely, 21 key nodes in the interactome are deregulated in AD. Interestingly, some of them are linked to beta-amyloid production and clearance. Thus, we inspected their role, along with their interactors, using the gene ontologies of the biological process that reveals their contribution in brain organization, immune response, oxidative stress and viral replication. We conclude that SARS-CoV-2 worsens the AD condition by increasing neurotoxicity, due to higher levels of beta-amyloid, inflammation and oxidative stress.

Chronic Rhinosinusitis and Alzheimer's Disease-A Possible Role for the Nasal Microbiome in Causing Neurodegeneration in the Elderly.

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.

The Effects of Aß1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2.

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer's disease (AD), the major form of dementia, ß-amyloid (Aß) levels in the blood are increased; however, the impact of elevated Aß levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aß1-42, but not Aß1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aß1-42. Furthermore, Aß1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aß1-42 show that the clearance of Aß1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aß antibody. In conclusion, these findings suggest that the binding of Aß1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aß1-42 in the blood is beneficial to the fight against COVID-19 and AD.

Editorial: Targets for Disease-Modifying Therapies in Alzheimer's Disease, Including Amyloid ß and Tau Protein.

Current treatments for patients with Alzheimer's disease aim to improve behavioral, cognitive, and non-cognitive symptoms. There have been no new drug approvals for preventing or treating Alzheimer's disease for more than two decades. Drug development in Alzheimer's disease aims to identify disease-modifying therapies that will delay or slow the clinical course of this disease. More than 50% of the current Alzheimer's disease drug pipeline now involves immunotherapies or oral small molecule agents. The most promising disease-modifying drug targets are amyloid ß and tau protein. In June 2021, aducanumab, a humanized recombinant monoclonal antibody to amyloid ß, was the first potential disease-modifying therapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer's disease and mild cognitive impairment. Accelerated approval of aducanumab was based on the results of only one of two phase 3 clinical trials. Several clinical trials of targeted disease-modifying immunotherapies to the tau protein and amyloid ß that commenced before the current COVID-19 pandemic have been delayed. This Editorial aims to provide an update on past, present, and future disease-modifying therapies in Alzheimer's disease, including targeted therapies for amyloid ß and tau protein.

NLRP3 and Infections: ß-Amyloid in Inflammasome beyond Neurodegeneration.

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.

SARS-CoV-2 spike protein interactions with amyloidogenic proteins: Potential clues to neurodegeneration.

The post-infection of COVID-19 includes a myriad of neurologic symptoms including neurodegeneration. Protein aggregation in brain can be considered as one of the important reasons behind the neurodegeneration. SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) binds to heparin and heparin binding proteins. Moreover, heparin binding accelerates the aggregation of the pathological amyloid proteins present in the brain. In this paper, we have shown that the SARS-CoV-2 S1 RBD binds to a number of aggregation-prone, heparin binding proteins including Aß, α-synuclein, tau, prion, and TDP-43 RRM. These interactions suggests that the heparin-binding site on the S1 protein might assist the binding of amyloid proteins to the viral surface and thus could initiate aggregation of these proteins and finally leads to neurodegeneration in brain. The results will help us to prevent future outcomes of neurodegeneration by targeting this binding and aggregation process.

Protein Expression of Angiotensin-Converting Enzyme 2 (ACE2) is Upregulated in Brains with Alzheimer's Disease.

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.