| 1. |
- Eidhof, Ilse, et al.
(författare)
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Unraveling the brain's response to COVID-19 : How SARS-CoV-2 afflicts dopaminergic neurons
- 2024
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Ingår i: Cell Stem Cell. - 1934-5909 .- 1875-9777. ; 31:2, s. 152-154
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 patients often display dysfunctions of the nervous system, indicating an effect of SARS-CoV-2 on neural cells. Yang et al. now show that human stem-cell-derived dopaminergic neurons are susceptible to SARS-CoV-2, triggering inflammation and senescence. The study further identifies three FDA-approved drugs capable of reversing these cellular phenotypes.
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| 2. |
- Giannisis,, Andreas, et al.
(författare)
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Brain integrity is altered by hepatic APOEε4 in humanized-liver mice
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes brain injury and neurodegeneration is unknown. Here we investigated the brains of Fah-/-, Rag2-/-, Il2rg-/- mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation, and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk neurodegenerative diseases.
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| 3. |
- Giannisis, Andreas, et al.
(författare)
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Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27:8, s. 3533-3543
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Tidskriftsartikel (refereegranskat)abstract
- Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah−/−, Rag2−/−, Il2rg−/− mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease.
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| 4. |
- Giannisis, Andreas, et al.
(författare)
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Plasma apolipoprotein E levels in longitudinally followed patients with mild cognitive impairment and Alzheimer's disease
- 2022
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Ingår i: Alzheimer's Research & Therapy. - : BioMed Central (BMC). - 1758-9193. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low levels of plasma apolipoprotein E (apoE) and presence of the APOE epsilon 4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE epsilon 4-carriers is well-established, the protein levels have received limited attention. Methods: We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 3 9), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 3 0) , patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and alpha-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6. Results: Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE epsilon 2/epsilon 3 versus APOE epsilon 4/epsilon 4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-beta (A beta(42)) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF A beta(42), lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF alpha-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed. Conclusions: Our results demonstrate important associations between low plasma apoE levels, A beta pathology, and progression from aMCI to a clinical ADD diagnosis.
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| 5. |
- Twohig, Daniel, et al.
(författare)
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alpha-synuclein in the pathophysiology of Alzheimer's disease
- 2019
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 14
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Forskningsöversikt (refereegranskat)abstract
- The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid- (A) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein -synuclein (Syn), mainly associated with synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), is involved in the pathophysiology of AD. Lewy-related pathology (LRP), primarily comprised of Syn, is present in a majority of autopsied AD brains, and higher levels of Syn in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD have been linked to cognitive decline. Recent studies also suggest that the asymptomatic accumulation of A plaques is associated with higher CSF Syn levels in subjects at risk of sporadic AD and in individuals carrying autosomal dominant AD mutations. Experimental evidence has further linked Syn mainly to tau hyperphosphorylation, but also to the pathological actions of A and the APOE epsilon 4 allele, the latter being a major genetic risk factor for both AD and DLB. In this review, we provide a summary of the current evidence proposing an involvement of Syn either as an active or passive player in the pathophysiological ensemble of AD, and furthermore describe in detail the current knowledge of Syn structure and inferred function.
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| 6. |
- Twohig, Daniel, 1976-
(författare)
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Apolipoprotein E and alpha-synuclein interactions, and their associations with neurodegenerative diseases
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The apolipoprotein E gene (APOE) is expressed as three major isoforms, APOE ε2, ε3 and ε4 that encode the apoE2, E3 and E4 proteins, respectively. APOE ε4 is associated with an increased risk for age-related neurodegenerative diseases including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), and increases the risk of dementia in Parkinson’s disease (PD), however, the exact molecular mechanisms underpinning the associations between APOE ε4 and neurodegeneration are still unknown. Pathologically, α-synuclein (αSyn) is the primary component of Lewy neuropathology which is stereotypically found in PD, DLB and also in the majority of AD brains upon post mortem examination, and changes in the soluble levels of intra- and extracellular αSyn in the central nervous system have been found in AD patients compared to cognitively healthy individuals. With this in mind, we hypothesized that interactions, both direct and indirect, between apoE4 / APOE ε4 and αSyn might help explain their associations with the pathogenesis of multiple neurodegenerative diseases. Using mouse models with a humanized APOE ε4/ε4 or ε3/ε3 liver genotype we found that changing the liver genotype to APOE ε4/ε4 led to a re-compartmentalization of brain αSyn and significant changes in key pre- and postsynaptic protein levels We also found that in prodromal sporadic AD patients APOE ε4 carriers had significantly increased cerebrospinal fluid (CSF) αSyn levels, and in autosomal dominant AD APOE ε4 carriers higher CSF αSyn levels that were correlated with AD-onset and increasing brain amyloid-β plaque deposition. When next assessing any disease related changes in the molecular sizes of αSyn and apoE in AD and PD post mortem brain parenchyma we found that the amygdala had a differing distribution of αSyn and apoE4 species. Co-incubation of the recombinant apoE isoforms and αSyn led to high molecular weight αSyn species, increased high molecular weight apoE2 species and a stabilized pool of monomeric apoE3. Using, binding kinetics assays and human neuronal cell cultures we found that recombinant apoE isoforms bind with similar strength to αSyn and reduce αSyn cellular uptake, whereas astrocyte secreted apoE led to an apoE- isoform-dependent reduction in αSyn uptake (apoE4 > apoE3 > apoE2). Further, heparin sulfate proteoglycans were partially responsible for αSyn uptake mediated by apoE. Taken together, our results show that APOE / apoE is linked to changes in levels, species and compartmentalization of αSyn in multiple pathological contexts ranging from the central nervus system to the periphery in humans, mouse models and cell lines. Our data reinforce the growing body of literature linking APOE / apoE and αSyn to the pathogenesis of the most prevalent neurodegenerative diseases.
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| 7. |
- Twohig, Daniel, 1976-, et al.
(författare)
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Molecular interactions between α-synuclein and apolipoprotein E isoforms
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ε4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for both Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Recent studies have shown that apoE4 promotes α-synuclein[J1] [DT2] pathology and that α-synuclein can be found in apoE-containing lipoprotein particles in human cerebrospinal fluid (CSF). To elucidate potential interactions between apoE isoforms and α-synuclein, we examined molecular interaction with microscale thermophoresis (MST), and assessed whether uptake of α-synuclein by cultured Lund human mesencephalic (LUHMES) neuronal progenitor cells can be modulated by apoE. We found that the dissociation constants (Kd) for apoE isoform interactions with α-synuclein ranged between 1.8 – 4.2 μM and did not differ between the apoE isoforms. Co-incubation of α-synuclein and recombinant apoE isoforms resulted in the generation of a pool of high molecular weight α-synuclein species and a reduction in α-synuclein monomers and dimers with apoE2 significantly reduced the amounts of a specific 55-kDa α-synuclein band. In turn, α-synuclein increased the levels of multimeric and high molecular weight apoE2 species, but decreased levels of apoE3 (but not apoE4) multimers by effectively stabilizing the apoE3 monomer pool in an opposite manner. Further, recombinant apoE isoforms reduced α-synuclein cellular uptake to a similar extent by approximately 20% whereas astrocyte-secreted apoE reduced cellular uptake in an apoE isoform-dependent manner (apoE2 ≤ apoE3 < apoE4). Our results demonstrate molecular interactions between apoE and α-synuclein that may result in altered cellular uptake of the latter, proposing apoE as a modulator of the extracellular pool of α-synuclein.
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| 8. |
- Twohig, Daniel, et al.
(författare)
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Molecular size distributions of apolipoprotein E and alpha-synuclein in post mortem cerebrospinal fluid and brain tissues from Alzheimer’s and Parkinson’s disease patients with an APOEε3/ε4 genotype
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The apolipoprotein E epsilon 4 allele (APOEε4) is the strongest genetic risk factor for both sporadic Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Carriers of APOEε4 have more abundant AD amyloid-β pathology, and recent findings further suggest that the allele promotes α‑synuclein (αSyn) pathology. We have previously described an APOEε4 dose-depended increase in cerebrospinal fluid (CSF) αSyn levels in prodromal AD patients and elevated levels of monomeric intracellular αSyn were reported in AD brains lacking Lewy pathology. Importantly, over 50% of sporadic AD patients exhibit notable levels of Lewy pathology and a majority of PSEN1 mutation-carrying familial AD patients exhibit αSyn pathology in the amygdala. Here we assessed the levels and molecular size distribution of αSyn, total apolipoprotein E (apoE), and apoE4 in ventricular CSF from APOEε3/ε4-carrying patients with AD and Parkinson’s disease (PD), and controls using size exclusion chromatography, ELISA and western blotting. We further assessed brain regional differences in the solubilities and molecular species of αSyn and apoE and apoE4 using tissue fractionation and western blotting. Levels of CSF apoE and apoE4 were lower in AD versus PD patients, while levels of CSF αSyn were generally higher than reported in ante mortem lumbar CSF samples. No notable co-elution of αSyn and apoE occurred in CSF. In the brain parenchyma, compared to the medial frontal gyrus and medial temporal gyrus, the amygdala had higher levels and more species of saline and Triton X‑100 soluble apoE4 and αSyn regardless of patient diagnosis. Overall, our results suggest that levels of postmortem CSF apoE and apoE4 are reduced in AD versus PD patients, and that the amygdala appears to have a unique, but not a disease-specific pattern of apoE4 and αSyn molecular species.
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| 9. |
- Twohig, Daniel, et al.
(författare)
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The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer's disease
- 2018
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) -synuclein (Syn) levels and Syn pathology in the brains of Alzheimer's disease (AD) patients suggests that Syn is involved in the pathophysiology of AD. To investigate whether Syn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of Syn and assessed links to various disease parameters in a longitudinally followed cohort (n=136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n=142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline Syn levels (p=0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p=0.02). In the same patients, there was a dose-dependent positive association between CSF Syn and the APOE epsilon 4 allele. Further, CSF Syn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p=0.03), and positively correlated to the estimated years from symptom onset (p=0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating<0.5) PET amyloid-positive ADAD mutation carriers CSF Syn was positively correlated to C-11-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOE epsilon 4-positive ADAD mutation carriers exhibited an association between CSF Syn levels and mean cortical PiB retention (p=0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of Syn, tau and amyloid-(1-40).Our results suggest that higher CSF Syn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOE epsilon 4 may promote the processes driven by Syn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development.
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