Journal of Alzheimer's Disease - Volume 83, issue 3

Authors: Van Zeller, Mariana | Dias, Diogo | Sebastião, Ana M. | Valente, Cláudia A.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range …of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, astrocytes, inflammasome, MCC950, neuroinflammation, NLRP3, microglia, pro-inflammatory cytokines, pyroptosis, tau

DOI: 10.3233/JAD-210268

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 939-961, 2021

Authors: Li, Yanli | Wang, Rui | Li, Qian | Wang, Yan-Jiang | Guo, Junhong

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive decline in cognitive function. Amyloid-β protein accumulation is believed to be the key pathological hallmark of AD. Increasing evidence has shown that the gut microbiota has a role in brain function and host behaviors. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine, and immune pathways. With increasing age, the gut microbiota diversity decreases, and the dominant bacteria change, which is closely related to systemic inflammation and health status. Dysbiosis of the gut microbiota is …related to cognitive impairment and neurodegenerative diseases. The purpose of this review is to discuss the impacts of the gut microbiota on brain function and the development of AD. It is a feasible target for therapeutic invention. Modulating the composition of the gut microbiota through diet, physical activity or probiotic/prebiotic supplements can provide new prevention and treatment options for AD. Show more

Keywords: Keywords: Alzheimer’s disease, dysbiosis, gut, microbiota, microbiota-gut-brain axis, pathophysiology, therapeutics

DOI: 10.3233/JAD-210381

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 963-976, 2021

Authors: Cioffi, Federica | Adam, Rayan Hassan Ibrahim | Bansal, Ruchi | Broersen, Kerensa

Article Type: Review Article

Abstract: Oxidative stress is associated with the progression of Alzheimer’s disease (AD). Reactive oxygen species can modify lipids, DNA, RNA, and proteins in the brain. The products of their peroxidation and oxidation are readily detectable at incipient stages of disease. Based on these oxidation products, various biomarker-based strategies have been developed to identify oxidative stress levels in AD. Known oxidative stress-related biomarkers include lipid peroxidation products F2-isoprostanes, as well as malondialdehyde and 4-hydroxynonenal which both conjugate to specific amino acids to modify proteins, and DNA or RNA oxidation products 8-hydroxy-2’-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively. The inducible enzyme heme oxygenase type …1 (HO-1) is found to be upregulated in response to oxidative stress-related events in the AD brain. While these global biomarkers for oxidative stress are associated with early-stage AD, they generally poorly differentiate from other neurodegenerative disorders that also coincide with oxidative stress. Redox proteomics approaches provided specificity of oxidative stress-associated biomarkers to AD pathology by the identification of oxidatively damaged pathology-specific proteins. In this review, we discuss the potential combined diagnostic value of these reported biomarkers in the context of AD and discuss eight oxidative stress-related mRNA biomarkers in AD that we newly identified using a transcriptomics approach. We review these genes in the context of their reported involvement in oxidative stress regulation and specificity for AD. Further research is warranted to establish the protein levels and their functionalities as well as the molecular mechanisms by which these potential biomarkers are involved in regulation of oxidative stress levels and their potential for determination of oxidative stress and disease status of AD patients. Show more

Keywords: Alzheimer’s disease, biomarkers, genes, mild cognitive impairment, oxidative stress, transcriptomics

DOI: 10.3233/JAD-210497

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 977-1001, 2021

Authors: Kaufmann, Liane | Moeller, Korbinian | Marksteiner, Josef

Article Type: Review Article

Abstract: Old age is critically associated with multi-morbidity, chronic pain, and high risk for dementia. Recognizing and treating pain is very much dependent on language comprehension and production. Both may be impaired in dementia. Moreover, neuropsychiatric symptoms may interact with pain perception. The main aims of the present article were 1) to identify key areas for future research to elucidate the relation between pain and associated neuropsychiatric symptoms in dementia, and 2) to provide a conceptual framework for ameliorating the clinical process of recognizing, assessing, and managing pain in non-communicating patients with advanced dementia.

Keywords: Dementia, diagnosis, neuropsychiatric symptoms, pain, research criteria, treatment

DOI: 10.3233/JAD-210263

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1003-1009, 2021

Authors: Agüero, Pablo | Sainz, María José | Téllez, Raquel | Lorda, Isabel | Ávila, Almudena | García-Ribas, Guillermo | Rodríguez, Patricia Paredes | Gómez-Tortosa, Estrella

Article Type: Short Communication

Abstract: We report a patient with sporadic Alzheimer’s disease with onset in his twenties found to carry the de novo Pro436Gln mutation in the presenilin 1 gene (PS1 ). Clinical phenotype featured a posterior cortical syndrome with severe visual agnosia and mild limb spasticity with brisk reflexes. Brain MRI and FDG-PET scans revealed severe parieto-occipital atrophy/hypometabolism. Cerebrospinal fluid biomarkers showed a decrease in Aβ42 level and Aβ42/40 ratio, increased phospho-tau, and normal total tau. Amyloid PET identified a very high burden of amyloid-β neuritic plaques in the posterior cortex. Similarities between this and two previously reported cases with …this variant support that this mutation has a very strong impact on the clinical phenotype and is consistently associated with spasticity. Show more

Keywords: Alzheimer’s disease, de novo mutation, early-onset dementia, presenilin 1 mutation, posterior cortical atrophy

DOI: 10.3233/JAD-210420

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1011-1016, 2021

Authors: Bentham, Peter | Staff, Roger T. | Schelter, Bjoern O. | Shiells, Helen | Harrington, Charles R. | Wischik, Claude M.

Article Type: Short Communication

Abstract: One of the mutations in the microtubule-associated protein tau, P301S, is causative for dominantly inherited frontotemporal dementia characterized by extensive tau pathology for which no licensed treatment is available. Hydromethylthionine is a potent tau aggregation inhibitor. We report treatment of an asymptomatic carrier of the P301S mutation using hydromethylthionine over a 5-year period beginning at the mean age of onset of clinical decline in the family. During the period of treatment, the rates of progression of cerebral atrophy were reduced by 61%–66% in frontal and temporal lobes, and the patient remained clinically asymptomatic.

Keywords: Frontotemporal dementia, hydromethylthionine, leucomethylthioninium, microtubule-associated protein tau, P301S

DOI: 10.3233/JAD-210390

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1017-1023, 2021

Authors: Kim, Hang-Rai | Jang, Ja Hyun | Ham, Honggi | Choo, Seung Ho | Park, Jeongho | Kang, Sung Hoon | Hwangbo, Song | Jang, Hyemin | Na, Duk L. | Seo, Sang Won | Baek, Ji Hyun | Kim, Hee Jin

Article Type: Short Communication

Abstract: Atypical psychological symptoms frequently occur in early-onset Alzheimer’s disease (EOAD), which makes it difficult to differentiate it from other psychiatric disorders. We report the case of a 28-year-old woman with EOAD, carrying a presenilin-1 mutation (S170P), who was initially misdiagnosed with schizophrenia because of prominent psychiatric symptoms in the first 1–2 years of the disease. Amyloid-β positron emission tomography (PET) showed remarkably high tracer uptake in the striatum and thalamus. Tau PET showed widespread cortical uptake and relatively low uptake in the subcortical and medial temporal regions. Our case advocates for considering EOAD diagnosis for young patients with psychiatric and …atypical cognitive symptoms. Show more

Keywords: Alzheimer’s disease, positron emission tomography, PSEN1 mutation, psychosis

DOI: 10.3233/JAD-210650

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1025-1031, 2021

Authors: Gouilly, Dominique | Tisserand, Camille | Nogueira, Leonor | Saint-Lary, Laura | Rousseau, Vanessa | Benaiteau, Marie | Rafiq, Marie | Carlier, Jasmine | Milongo-Rigal, Emilie | Pagès, Jean-Christophe | Pariente, Jérémie

Article Type: Short Communication

Abstract: The consistency of cerebrospinal fluid amyloid-β (Aβ)42/40 ratio and Aβ42 has not been assessed in the AT(N) classification system. We analyzed the classification changes of the dichotomized amyloid status (A+/A–) in 363 patients tested for Alzheimer’s disease biomarkers after Aβ42 was superseded by the Aβ42/40 ratio. The consistency of Aβ42 and the Aβ42/40 ratio was very low. Notably, the proportions of “false” A+T–patients were considerable (74–91%) and corresponded mostly to patients not clinically diagnosed with Alzheimer’s disease. Our results suggest that the interchangeability of Aβ42/40 ratio and Aβ42 is limited for classifying …patients in clinical setting using the AT(N) scheme. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, lumbar puncture

DOI: 10.3233/JAD-210236

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1033-1038, 2021

Authors: Pope, Chad A. | Wilkins, Heather M. | Swerdlow, Russell H. | Wolfe, Michael S.

Article Type: Research Article

Abstract: Background: Dominant missense mutations in the amyloid-β protein precursor (AβPP) cause early-onset familial Alzheimer’s disease (FAD) and are associated with changes in the production or properties of the amyloid-β peptide (Aβ), particularly of the 42-residue variant (Aβ42 ) that deposits in the Alzheimer’s disease (AD) brain. Recent findings, however, show that FAD mutations in AβPP also lead to increased production of longer Aβ variants of 45–49 residues in length. Objective: We aimed to test neurotoxicity of Aβ42 vis-á-vis longer variants, focusing specifically on mitochondrial function, as dysfunctional mitochondria are implicated in the pathogenesis of AD. …Methods: We generated SH-SY5Y human neuroblastoma cells stably expressing AβPP mutations that lead to increased production of long Aβ peptides with or without Aβ42 . These AβPP-expressing cells were tested for oxygen consumption rates (OCR) under different conditions designed to interrogate mitochondrial function. These cell lines were also examined for expression of genes important for mitochondrial or neuronal structure and function. Results: The mutant AβPP-expressing cells showed decreased basal OCRs as well as decreased OCRs associated with mitochondrial ATP production, even more so in the absence of Aβ42 production. Moreover, mutant AβPP-expressing cells producing longer forms of Aβ displayed altered expression of certain mitochondrial- and neuronal-associated genes, whether or not Aβ42 was produced. Conclusion: These findings suggest that mutant AβPP can cause mitochondrial dysfunction that is associated with long Aβ but not with Aβ42 . Show more

Keywords: ATP, ELISAs, mutagenesis, oxygen consumption rates, RNA analysis

DOI: 10.3233/JAD-210366

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1039-1049, 2021

Authors: Jorda, Adrián | Aldasoro, Martin | Aldasoro, Constanza | Valles, Soraya L.

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), an increase in inflammation is distinctive. Amyloid precursor protein plus presenilin-1 (APP/PS1 mice) is a model for this illness. Chemokines secreted by central nervous system (CNS) cells could play multiple important roles in AD. Data looking for the chemokines involved in inflammatory mechanisms are lacking. To understand the changes that occur in the inflammation process in AD, it is necessary to improve strategies to act on specific inflammatory targets. Objective: Chemokines and their receptors involved in phagocytosis, demyelination, chemotaxis, and coagulation were the objective of our study. Methods: Female APPswe/PS1 double-transgenic …mice (B6C3-Tg) were used and cortex brain from 20–22-month-old mice obtained and used to quantify chemokines and chemokine receptors expression using RT-PCR technique. Results: Significant inflammatory changes were detected in APP/PS1 compared to wild type mice. CCR1, CCR3, CCR4, and CCR9 were elevated, and CCR2 were decreased compared with wild type mice. Their ligands CCL7, CCL11, CCL17, CCL22, CCL25, and CXCL4 showed an increase expression; however, changes were not observed in CCL2 in APP/PS1 compared to wild type mice. Conclusion: This change in expression could explain the differences between AD patients and elderly people without this illness. This would provide a new strategy for the treatment of AD, with the possibility to act in specific inflammatory targets. Show more

Keywords: Alzheimer’s disease, APP/PS1, chemokine receptors, chemokines, inflammation

DOI: 10.3233/JAD-210489

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1051-1060, 2021