| 1. |
|
|
| 2. |
- Brown, J., et al.
(författare)
-
Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations
- 2023
-
Ingår i: Acta Neuropathologica Communications. - 2051-5960. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) and other tauopathies are characterized by the aggregation of tau into soluble and insoluble forms (including tangles and neuropil threads). In humans, a fraction of both phosphorylated and non-phosphorylated N-terminal to mid-domain tau species, are secreted into cerebrospinal fluid (CSF). Some of these CSF tau species can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. While in animal models of AD pathology, soluble tau aggregates have been shown to disrupt neuronal function, it is unclear whether the tau species present in CSF will modulate neural activity. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function, from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input-output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future.
|
|
| 3. |
- Camporesi, Elena
(författare)
-
Candidate biomarkers for synaptic pathology: neurogranin, neuroligins and neurexins in neurodegenerative disorders
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Synapses are small units through which neurons communicate in the brain. They represent the site of memory formation and cognitive abilities and are thus primarily affected by neurodegenerative diseases such as Alzheimer’s disease (AD), the leading cause of dementia in the elderly population. Despite great research efforts, there is no definitive cure to date. Moreover, AD diagnosis is challenged by comorbidities and the long prodromal asymptomatic disease stage that conceal early pathological changes in the brain. These pathological changes affect synapse structure and function and cause the cognitive decline observed in AD and other neurodegenerative diseases. Furthermore, synaptic degeneration has been described as an early event in AD and as a better correlate of the degree of cognitive decline or disease severity than e.g., amyloid-β deposits, a major pathological hallmarks of AD. For these reasons, synaptic proteins are considered candidate biomarkers for the detection of early pathological changes in AD and to track cognitive decline. The study of synaptic proteins is further important to understand pathological events affecting synapses and to discover novel biomarkers to detect such changes. In this thesis, we investigated the postsynaptic proteins neurogranin (Ng) and neuroligins (Nlgn) in brain tissue and cerebrospinal fluid (CSF), focusing on AD. These initial investigations were expanded to include the presynaptic binding partners of Nlgns, the neurexins (NRXN), to gain an overview of changes of this class of synaptic adhesion proteins in neurodegenerative diseases. The aim was to identify changes in concentration and fragmentation patterns of these proteins during AD and to evaluate the usefulness of NRXNs and Nlgns as biomarkers for synaptic pathology in neurodegenerative diseases, primarily AD. The investigation into proteolytic processing of Ng led to the identification of two enzymes that can cleave the protein, probably in sequence, generating the C-terminal Ng’s fragments previously described to appear in increased levels in the CSF of AD patients. Additionally, CSF was found to contain full-length Ng of different molecular forms and new N-terminal fragments. These studies revealed the complexity of Ng’s processing during AD and open up for further investigations of the potential utility of these new species as biomarkers for synaptic pathology in AD. The study of the transmembrane proteins Nlgn and NRXN were directed toward their soluble extracellular fragments, which are cleaved off and released in response to synaptic activity. Initial investigations for Nlgn1 showed that its fragment levels were decreased in different brain regions in AD. However, the greatest differences were found in frontal grey matter of a group of primary tauopathies, showing marked reductions, results that encourage further investigations of the protein in those diseases. The simultaneous quantification of Nlgns and NRXNs with a targeted parallel reaction monitoring mass spectrometry method in CSF revealed no changes in the levels of the targeted protein fragments along the disease continuum, suggesting that these proteins do not reflect synaptic dysfunction during AD. In conclusion, the research conducted in this thesis has increased our understanding of the role of the processing of the synaptic proteins Ng, Nlgns and NRXNs and provides the groundwork for future investigations of those proteins in AD and other neurodegenerative diseases. Furthermore, they will inform the development of new tools to monitor synaptic dysfunction and increase the interpretability of those proteins as biomarkers in neurodegenerative diseases.
|
|
| 4. |
- Camporesi, Elena, et al.
(författare)
-
Fluid Biomarkers for Synaptic Dysfunction and Loss
- 2020
-
Ingår i: Biomarker Insights. - : SAGE Publications. - 1177-2719. ; 15
-
Tidskriftsartikel (refereegranskat)abstract
- Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer's disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and alpha-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.
|
|
| 5. |
- Camporesi, Elena, et al.
(författare)
-
Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers
- 2021
-
Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Synaptic pathology is a central event in Alzheimer's disease (AD) and other neurodegenerative conditions, and investigation of synaptic proteins can provide valuable tools to follow synaptic dysfunction and loss in these diseases. Neuroligin-1 (Nlgn1) is a postsynaptic cell adhesion protein, important for synapse stabilization and formation. Nlgn1 has been connected to cognitive disorders, and specifically to AD, as target of the synaptotoxic effect of amyloid-beta (A beta) oligomers and A beta fibrils. To address changes in Nlgn1 expression in human brain, brain regions in different neurological disorders were examined by Western blot and mass spectrometry. Brain specimens from AD (n = 23), progressive supranuclear palsy (PSP, n = 11), corticobasal degeneration (CBD, n = 10), and Pick's disease (PiD, n = 9) were included. Additionally, cerebrospinal fluid (CSF) samples of AD patients (n = 43) and non-demented controls (n = 42) were analysed. We found decreased levels of Nlgn1 in temporal and parietal cortex (similar to 50-60% reductions) in AD brains compared with controls. In frontal grey matter the reduction was not seen for AD patients; however, in the same region, marked reduction was found for PiD (similar to 77%), CBD (similar to 66%) and to a lesser extent for PSP (similar to 43%), which could clearly separate these tauopathies from controls. The Nlgn1 level was reduced in CSF from AD patients compared to controls, but with considerable overlap. The dramatic reduction of Nlgn1 seen in the brain extracts of tauopathies warrants further investigation regarding the potential use of Nlgn1 as a biomarker for these neurodegenerative diseases.
|
|
| 6. |
- Camporesi, Elena, et al.
(författare)
-
Quantification of the trans-synaptic partners neurexin-neuroligin in CSF of neurodegenerative diseases by parallel reaction monitoring mass spectrometry
- 2022
-
Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 75
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Synaptic proteins are increasingly studied as biomarkers for synaptic dysfunction and loss, which are early and central events in Alzheimer's disease (AD) and strongly correlate with the degree of cognitive decline. In this study, we specifically investigated the synaptic binding partners neurexin (NRXN) and neuroligin (Nlgn) proteins, to assess their biomarker's potential. Methods: we developed a parallel reaction monitoring mass spectrometric method for the simultaneous quantification of NRXNs and Nlgns in cerebrospinal fluid (CSF) of neurodegenerative diseases, focusing on AD. Specifically, NRXN-1α, NRXN-1β, NRXN-2α, NRXN-3α and Nlgn1, Nlgn2, Nlgn3 and Nlgn4 proteins were targeted. Findings: The proteins were investigated in a clinical cohort including CSF from controls (n=22), mild cognitive impairment (MCI) due to AD (n=44), MCI due to other conditions (n=46), AD (n=77) and a group of non-AD dementia (n=28). No difference in levels of NRXNs and Nlgns was found between AD (both at dementia and MCI stages) or controls or the non-AD dementia group for any of the targeted proteins. NRXN and Nlgn proteins correlated strongly with each other, but only a weak correlation with the AD core biomarkers and the synaptic biomarkers neurogranin and growth-associated protein 43, was found, possibly reflecting different pathogenic processing at the synapse. Interpretation: we conclude that NRXN and Nlgn proteins do not represent suitable biomarkers for synaptic pathology in AD. The panel developed here could aid in future investigations of the potential involvement of NRXNs and Nlgns in synaptic dysfunction in other disorders of the central nervous system. Funding: a full list of funding can be found under the acknowledgments section. © 2021 The Author(s)
|
|
| 7. |
- Hanbouch, L., et al.
(författare)
-
Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic A beta Peptides
- 2022
-
Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 59, s. 7056-7073
-
Tidskriftsartikel (refereegranskat)abstract
- Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-beta peptides A beta 40 and A beta 42 secretion from transiently transfected HEK293T cells. Only the mutations at position 28 of A beta in the APP sequence resulted in a concomitant significant increase in the production of shorter A beta peptides. Mass spectrometry (MS) confirmed the predominance of A beta x-33 and A beta x-34 with the APP(K28A) mutant. The enzymatic activity of alpha-, beta-, and gamma-secretases remained unchanged in cells expressing all mutants. Similarly, subcellular localization of the mutants in early endosomes did not differ from the APP(WT) protein. A transient increase of plasma membrane cholesterol enhanced the production of A beta 40 and A beta 42 by APP(WT), an effect absent in APP(K28A) mutant. Finally, WT but not CBS mutant A beta derived peptides bound to cholesterol-rich exosomes. Collectively, the present data revealed a major role of juxtamembrane amino acids of the APP CBS in modulating the production of toxic A beta species. More generally, they underpin the role of cholesterol in the pathophysiology of AD.
|
|
| 8. |
- Kac, Przemyslaw R., et al.
(författare)
-
Plasma p-tau212: antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.
- 2023
-
Ingår i: medRxiv : the preprint server for health sciences.
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Thereafter, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n=388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a novel peripherally accessible biomarker of AD pathophysiology.
|
|
| 9. |
- Kac, Przemyslaw R., 1995, et al.
(författare)
-
Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.
- 2024
-
Ingår i: Nature communications. - 2041-1723. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n=388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.
|
|
| 10. |
- Lantero Rodriguez, Juan, et al.
(författare)
-
P-tau235: a novel biomarker for staging preclinical Alzheimer's disease.
- 2021
-
Ingår i: EMBO molecular medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 13:12
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p-tau) species such as p-tau217 and p-tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p-tau235 is a prominent feature of AD pathology. In addition, p-tau235 seemed to be preceded by p-tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p-tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p-235 increases early in AD continuum, and (ii) changes in CSF p-tau235 and p-tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p-tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.
|
|
