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1.
Mol Diagn Ther ; 2024 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-39316339

RESUMEN

Until recently, only symptomatic therapies, in the form of acetylcholine esterase inhibitors and NMDA-receptor antagonists, have been available for the treatment of Alzheimer's disease. However, advancements in our understanding of the amyloid cascade hypothesis have led to a development of disease-modifying therapeutic strategies. These include immunotherapies based on an infusion of monoclonal antibodies against amyloid-ß, three of which have been approved for the treatment of Alzheimer's disease in the USA (one of them, lecanemab, has also been approved in several other countries). They all lead to a dramatic reduction of amyloid plaques in the brain, whereas their clinical effects have been more limited. Moreover, they can all lead to side effects in the form of amyloid-related imaging abnormalities. Ongoing developments aim at facilitating their administration, further improving their effects and reducing the risk for amyloid-related imaging abnormalities. Moreover, a number of anti-tau immunotherapies are in clinical trials, but none has so far shown any robust effects on symptoms or pathology. Another line of development is represented by gene therapy. To date, only antisense oligonucleotides against amyloid precursor protein/amyloid-ß and tau have reached the clinical trial stage but a variety of gene editing strategies, such as clustered regularly interspaced short palindromic repeats/Cas9-mediated non-homologous end joining, base editing, and prime editing, have all shown promise on preclinical disease models. In addition, a number of other pharmacological compounds targeting a multitude of biochemical processes, believed to be centrally involved in Alzheimer's disease, are currently being evaluated in clinical trials. This article delves into current and future perspectives on the treatment of Alzheimer's disease, with an emphasis on immunotherapeutic and gene therapeutic strategies.

2.
Front Neurosci ; 18: 1436262, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39161653

RESUMEN

Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation of such proteins in diseased brains is believed to be the end-stage of a stepwise aggregation of misfolded monomers to insoluble cross-ß fibrils via a series of differently sized soluble oligomers/protofibrils. Several studies have shown how α-synuclein, amyloid-ß, tau and other amyloidogenic proteins can act as nucleating particles and thereby share properties with misfolded forms, or strains, of the prion protein. Although the roles of different protein assemblies in the respective aggregation cascades remain unclear, oligomers/protofibrils are considered key pathogenic species. Numerous observations have demonstrated their neurotoxic effects and a growing number of studies have indicated that they also possess seeding properties, enabling their propagation within cellular networks in the nervous system. The seeding behavior of oligomers differs between the proteins and is also affected by various factors, such as size, shape and epitope presentation. Here, we are providing an overview of the current state of knowledge with respect to the "prion-like" behavior of soluble oligomers for several of the amyloidogenic proteins involved in neurodegenerative diseases. In addition to providing new insight into pathogenic mechanisms, research in this field is leading to novel diagnostic and therapeutic opportunities for neurodegenerative diseases.

3.
Acta Neuropathol Commun ; 12(1): 22, 2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-38317196

RESUMEN

Deposition of amyloid beta (Aß) into plaques is a major hallmark of Alzheimer's disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aß. We recently identified the Uppsala APP mutation (APPUpp), which causes Aß pathology by a triple mechanism: increased ß-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aß conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aß pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aß pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased ß-secretase cleavage and suppressed α-secretase cleavage, resulting in AßUpp42 dominated diffuse plaque pathology appearing from the age of 5-6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aß pathology in all models, whereas the Aß protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aß pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AßUpp42 aggregates were found to affect their interaction with anti-Aß antibodies and profoundly modify the Aß-mediated glial response, which may be important aspects to consider for further development of AD therapies.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Animales , Humanos , Ratones , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Gliosis/patología , Ligandos , Ratones Transgénicos
4.
Acta Neuropathol Commun ; 12(1): 34, 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38409026

RESUMEN

Accumulating evidence highlights the involvement of astrocytes in Alzheimer's disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes' processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Proteínas tau/metabolismo , Encéfalo/patología , Neuronas/metabolismo , Inflamación/metabolismo
5.
PLoS One ; 19(2): e0297575, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38300935

RESUMEN

Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.


Asunto(s)
Disfunción Cognitiva , Humanos , Anciano , Reproducibilidad de los Resultados , Suecia , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Pruebas Neuropsicológicas , Cognición , Internet
7.
Circ Genom Precis Med ; 16(6): e004233, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38014560

RESUMEN

BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs. METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure. RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors. CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin were novel early markers of CVD. A selection of 11 proteins improved the discrimination of CVD.


Asunto(s)
Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Infarto del Miocardio , Accidente Cerebrovascular , Masculino , Adulto , Humanos , Enfermedades Cardiovasculares/diagnóstico , Estudios Longitudinales , Estudios Prospectivos , Proteómica , Activador de Plasminógeno de Tipo Uroquinasa , Infarto del Miocardio/epidemiología , Infarto del Miocardio/genética , Accidente Cerebrovascular/diagnóstico , Obesidad
8.
Cell Rep ; 42(11): 113395, 2023 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-37967557

RESUMEN

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.


Asunto(s)
Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Retrovirus Endógenos , Humanos , Animales , Ratones , Retrovirus Endógenos/genética , Enfermedades Neuroinflamatorias , Transcriptoma/genética , Lesiones Traumáticas del Encéfalo/patología , Lesiones Encefálicas/patología , Oligodendroglía/patología , Inflamación/genética , Inflamación/patología , Ratones Endogámicos C57BL
9.
Nat Neurosci ; 26(12): 2073-2080, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37973869

RESUMEN

The use of transgenic mice displaying amyloid-ß (Aß) brain pathology has been essential for the preclinical assessment of new treatment strategies for Alzheimer's disease. However, the properties of Aß in such mice have not been systematically compared to Aß in the brains of patients with Alzheimer's disease. Here, we determined the structures of nine ex vivo Aß fibrils from six different mouse models by cryogenic-electron microscopy. We found novel Aß fibril structures in the APP/PS1, ARTE10 and tg-SwDI models, whereas the human type II filament fold was found in the ARTE10, tg-APPSwe and APP23 models. The tg-APPArcSwe mice showed an Aß fibril whose structure resembles the human type I filament found in patients with sporadic Alzheimer's disease. A detailed assessment of the Aß fibril structure is key to the selection of adequate mouse models for the preclinical development of novel plaque-targeting therapeutics and positron emission tomography imaging tracers in Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Ratones , Animales , Enfermedad de Alzheimer/patología , Microscopía por Crioelectrón , Péptidos beta-Amiloides/metabolismo , Ratones Transgénicos , Encéfalo/metabolismo , Modelos Animales de Enfermedad
10.
Fluids Barriers CNS ; 20(1): 72, 2023 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-37833765

RESUMEN

BACKGROUND: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH. METHODS: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number. RESULTS: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91. CONCLUSIONS: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnostic potential in the work-up of patients with iNPH.


Asunto(s)
Enfermedad de Alzheimer , Hidrocéfalo Normotenso , Enfermedades Neurodegenerativas , Humanos , Péptidos beta-Amiloides , Hidrocéfalo Normotenso/diagnóstico , Proteínas tau , Citocinas , Antígeno B7-H1 , Biomarcadores
11.
Acta Neuropathol Commun ; 11(1): 97, 2023 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-37330529

RESUMEN

Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Humanos , Proteínas tau/metabolismo , Astrocitos/metabolismo , Tauopatías/patología , Enfermedad de Alzheimer/patología , Neuronas/metabolismo , Encéfalo/patología
12.
Cell Mol Neurobiol ; 43(6): 3023-3035, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37130995

RESUMEN

Growing evidence indicates that the pathological alpha-synuclein (α-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic α-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by α-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either α-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added α-syn on SNARE protein distribution. Long-term exposure to α-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) α-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with α-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 α-syn being formed. Taken together, our results demonstrate that different α-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.


Asunto(s)
Proteína 2 de Membrana Asociada a Vesículas , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Proteína 2 de Membrana Asociada a Vesículas/metabolismo , Proteínas SNARE , Neuronas/metabolismo , Proteínas Qa-SNARE
13.
Acta Neuropathol Commun ; 11(1): 72, 2023 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-37138318

RESUMEN

Unique strains of α-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial α-synuclein inclusions, α-synuclein aggregates in Parkinson's disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding α-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD α-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced α-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing α-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of α-synuclein aggregates in restricted regions of the brain. The induced α-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating α-synuclein strain that more closely resembles α-synuclein aggregates associated with PD than MSA.


Asunto(s)
Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Sinucleinopatías , Humanos , Ratones , Animales , alfa-Sinucleína/genética , alfa-Sinucleína/química , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patología , Mutación/genética , Sinucleinopatías/genética , Ratones Transgénicos
14.
J Transl Med ; 21(1): 270, 2023 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-37081484

RESUMEN

BACKGROUND: Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover new modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickness of a tissue slice. This may, in turn, negatively affect comprehensive capturing the transcriptomics profile in a single slice, especially for tissues having large differences in the size of nuclei. METHODS: Here, we defined the effect of Consecutive Slices Data Integration (CSDI) on unveiling accurate spot clustering and deconvolution of spatial transcriptomic spots in human postmortem brains. By considering the histological information as reference, we assessed the improvement of unsupervised clustering and single nuclei RNA-seq and ST data integration before and after CSDI. RESULTS: Apart from the escalated number of defined clusters representing neuronal layers, the pattern of clusters in consecutive sections was concordant only after CSDI. Besides, the assigned cell labels to spots matches the histological pattern of tissue sections after CSDI. CONCLUSION: CSDI can be applied to investigate consecutive sections studied with ST in the human cerebral cortex, avoiding misinterpretation of spot clustering and annotation, increasing accuracy of cell recognition as well as improvement in uncovering the layers of grey matter in the human brain.


Asunto(s)
Perfilación de la Expresión Génica , Transcriptoma , Humanos , Transcriptoma/genética , RNA-Seq , Encéfalo , Comunicación Celular
15.
Front Mol Biosci ; 10: 1080112, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36793785

RESUMEN

Introduction: Parkinson's disease and type 2 diabetes have both elements of local amyloid depositions in their pathogenesis. In Parkinson's disease, alpha-synuclein (aSyn) forms insoluble Lewy bodies and Lewy neurites in brain neurons, and in type 2 diabetes, islet amyloid polypeptide (IAPP) comprises the amyloid in the islets of Langerhans. In this study, we assessed the interaction between aSyn and IAPP in human pancreatic tissues, both ex vivo and in vitro. Material and Methods: The antibody-based detection techniques, proximity ligation assay (PLA), and immuno-TEM were used for co-localization studies. Bifluorescence complementation (BiFC) was used for interaction studies between IAPP and aSyn in HEK 293 cells. The Thioflavin T assay was used for studies of cross-seeding between IAPP and aSyn. ASyn was downregulated with siRNA, and insulin secretion was monitored using TIRF microscopy. Results: We demonstrate intracellular co-localization of aSyn with IAPP, while aSyn is absent in the extracellular amyloid deposits. ASyn reactivity is present in the secretory granules of ß-cells and some α-cells in human islets. The BiFC-expression of aSyn/aSyn and IAPP/IAPP in HEK293 cells resulted in 29.3% and 19.7% fluorescent cells, respectively, while aSyn/IAPP co-expression resulted in ∼10% fluorescent cells. Preformed aSyn fibrils seeded IAPP fibril formation in vitro, but adding preformed IAPP seeds to aSyn did not change aSyn fibrillation. In addition, mixing monomeric aSyn with monomeric IAPP did not affect IAPP fibril formation. Finally, the knockdown of endogenous aSyn did not affect ß cell function or viability, nor did overexpression of aSyn affect ß cell viability. Discussion: Despite the proximity of aSyn and IAPP in ß-cells and the detected capacity of preformed aSyn fibrils to seed IAPP in vitro, it is still an open question if an interaction between the two molecules is of pathogenic significance for type 2 diabetes.

16.
Brain ; 146(3): 1065-1074, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35552610

RESUMEN

Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA. This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion. Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Humanos , alfa-Sinucleína/metabolismo , Atrofia de Múltiples Sistemas/patología , Estudios Transversales , Enfermedad de Parkinson/patología , Células de Schwann , Biomarcadores , Enfermedad por Cuerpos de Lewy/metabolismo
17.
Proc Natl Acad Sci U S A ; 119(46): e2212954119, 2022 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-36343257

RESUMEN

Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer's disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aß and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aß and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aß and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aß and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aß and tau prions increased with age. In contrast to DS brains, the levels of Aß and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.


Asunto(s)
Enfermedad de Alzheimer , Síndrome de Down , Priones , Adulto , Humanos , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Estudios Transversales , Síndrome de Down/patología , Priones/metabolismo , Proteínas tau/metabolismo
18.
J Alzheimers Dis ; 90(4): 1601-1614, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36314207

RESUMEN

BACKGROUND: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed. OBJECTIVE: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer's disease (sAD). METHODS: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations. RESULTS: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations. CONCLUSION: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Anciano , Presenilina-1/genética , Presenilina-1/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/patología , Mutación/genética
19.
Pharmaceutics ; 14(7)2022 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-35890306

RESUMEN

Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson's disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology.

20.
Brain Behav ; 12(7): e2628, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35652155

RESUMEN

BACKGROUND: Intracellular deposition of alpha-synuclein (α-syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. Transgenic mouse models overexpressing human α-syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop α-syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of α-syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions. PURPOSE: One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within-group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD-related symptoms in such studies. METHODS: We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) α-syn in the context of their validity and utility for different types of behavioral studies. CONCLUSIONS: By applying appropriate behavioral tests, α-syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other α-synucleinopathies.


Asunto(s)
Enfermedad de Parkinson , Sinucleinopatías , Animales , Modelos Animales de Enfermedad , Humanos , Cuerpos de Lewy/patología , Ratones , Ratones Transgénicos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Sinucleinopatías/genética , alfa-Sinucleína/genética
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