| 1. |
- Bergh, Sofia, et al.
(författare)
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Effects of mutant huntingtin in oxytocin neurons on non-motor features of Huntington's disease
- 2023
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 49:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early non-motor features including anxiety, depression and altered social cognition are present in Huntington's disease (HD). The underlying neurobiological mechanisms are not known. Oxytocin (OXT) is involved in the regulation of emotion, social cognition and metabolism, and our previous work showed that the OXT system is affected early in HD. The aim of the study was to investigate the potential causal relationship between the selective expression of mutant huntingtin (mHTT) in OXT neurons and the development of non-motor features and neuropathology. Methods: To express mHTT only in OXT neurons, we used a novel flex-switch adeno-associated viral vector design to selectively express either mHTT or wild-type HTT in the paraventricular nucleus of the hypothalamus using OXT-Cre-recombinase mice. We also performed a mirror experiment to selectively delete mHTT in OXT neurons using the BACHD mouse model. Mice underwent a battery of behavioural tests to assess psychiatric and social behaviours 3 months post-injection or at 2 months of age, respectively. Post-mortem analyses were performed to assess the effects on the OXT system. Results: Our results show that selective expression of mHTT in OXT neurons was associated with the formation of mHTT inclusions and a 26% reduction of OXT-immunopositive neurons as well as increased anxiety-like behaviours compared with uninjected mice. However, selective deletion of mHTT from OXT neurons alone was not sufficient to alter the metabolic and psychiatric phenotype of the BACHD mice at this early time point. Conclusions: Our results indicate that mHTT expression can exert cell-autonomous toxic effects on OXT neurons without affecting the non-motor phenotype at early time points in mice.
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| 2. |
- Cheong, Rachel Y., et al.
(författare)
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Effects of mutant huntingtin inactivation on Huntington disease-related behaviours in the BACHD mouse model
- 2021
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 47:4, s. 564-578
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Huntington disease (HD) is a fatal neurodegenerative disorder with no disease-modifying treatments approved so far. Ongoing clinical trials are attempting to reduce huntingtin (HTT) expression in the central nervous system (CNS) using different strategies. Yet, the distribution and timing of HTT-lowering therapies required for a beneficial clinical effect is less clear. Here, we investigated whether HD-related behaviours could be prevented by inactivating mutant HTT at different disease stages and to varying degrees in an experimental model. Methods: We generated mutant BACHD mice with either a widespread or circuit-specific inactivation of mutant HTT by using Cre recombinase (Cre) under the nestin promoter or the adenosine A2A receptor promoter respectively. We also simulated a clinical gene therapy scenario with allele-specific HTT targeting by injections of recombinant adeno-associated viral (rAAV) vectors expressing Cre into the striatum of adult BACHD mice. All mice were assessed using behavioural tests to investigate motor, metabolic and psychiatric outcome measures at 4–6 months of age. Results: While motor deficits, body weight changes, anxiety and depressive-like behaviours are present in BACHD mice, early widespread CNS inactivation during development significantly improves rotarod performance, body weight changes and depressive-like behaviour. However, conditional circuit-wide mutant HTT deletion from the indirect striatal pathway during development and focal striatal-specific deletion in adulthood failed to rescue any of the HD-related behaviours. Conclusions: Our results indicate that widespread targeting and the timing of interventions aimed at reducing mutant HTT are important factors to consider when developing disease-modifying therapies for HD.
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| 3. |
- Espinosa-Oliva, Ana M., et al.
(författare)
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Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain
- 2024
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In: Neuropathology and Applied Neurobiology. - 0305-1846. ; 50:1
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Journal article (peer-reviewed)abstract
- Aims: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons. Methods: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology. Results: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD. Conclusion: These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.
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| 4. |
- Gabery, Sanaz, et al.
(author)
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Loss of the metabolism and sleep regulating neuronal populations expressing orexin and oxytocin in the hypothalamus in amyotrophic lateral sclerosis
- 2021
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In: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 47:7, s. 979-989
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Journal article (peer-reviewed)abstract
- Aims: To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease. Methods: The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression. Results: Tar DNA-binding protein 43 (TDP-43) inclusions were present in the hypothalamus of all patients with amyotrophic lateral sclerosis. When compared to controls, there was atrophy of the hypothalamus (average 21% atrophy, p = 0.004), PVN (average 30% atrophy p = 0.014) and a loss of paraventricular oxytocin-producing neurons (average 49% loss p = 0.02) and lateral hypothalamic orexin-producing neurons (average 37% loss, significance p = 0.02). Factor analysis identified strong relationships between abnormal eating behaviour, hypothalamic atrophy and loss of orexin-producing neurons. With increasing disease progression, abnormal sleep behaviour and cognition associated with atrophy of the fornix. Conclusions: Substantial loss of hypothalamic oxytocin-producing neurons occurs in ALS, with regional atrophy and the loss of orexin neurons relating to abnormal eating behaviour in ALS. Oxytocin- and orexin neurons display TDP43 inclusions. Our study points to significant pathology in the hypothalamus that may play a key role in metabolic and pathogenic changes in ALS.
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| 8. |
- Libard, Sylwia, et al.
(author)
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Is islet amyloid polypeptide indeed expressed in the human brain?
- 2023
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In: Neuropathology and Applied Neurobiology. - : John Wiley & Sons. - 0305-1846 .- 1365-2990. ; 49:4
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Journal article (peer-reviewed)abstract
- Aims This study aims to study the association between pancreatic islet amyloid polypeptide (IAPP) and Alzheimer's disease neuropathological change (ADNC) in brain biopsies obtained from subjects with idiopathic normal pressure hydrocephalus (iNPH) and in post-mortem (PM) brain samples obtained from aged individuals.Methods For the immunohistochemical (IHC) analyses, two IAPP antibodies (Abs), monoclonal and polyclonal, and Abs directed towards ADNC were applied.Results The iNPH cohort included 113 subjects. Amyloid-& beta; (A & beta;) was detected in 50% and hyperphosphorylated & tau; (HP & tau;) in 47% of the cases. Concomitant pathology was seen in 32%. The PM cohort included 77 subjects. A & beta; was detected in 69% and HP & tau; in 91% of the cases. Combined A & beta;/HP & tau; pathology was seen in 62%. Reactivity for the monoclonal IAPP was not detected in the brain tissue in either of the cohorts. Reactivity for the polyclonal IAPP was observed in all 77 PM brain samples.Conclusions There was no specific expression of IAPP in human brain tissue; hence, an association between IAPP and ADNC is not assessable. Of note, the observed reactivity of the polyclonal IAPP Ab was not reproduced with a specific monoclonal Ab; thus, we considered the observed staining with the polyclonal Ab to be unreliable. When using IHC, several pitfalls, especially the choice of an Ab, always need to be considered. Polyclonal Abs cross-react with other epitopes and proteins, thus leading to false-positive results. This seems to be the case for the polyclonal IAPP Abs in the human brain.
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| 9. |
- Manojlovic-Gacic, E, et al.
(author)
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Invited Review: Pathology of pituitary neuroendocrine tumours : present status, modern diagnostic approach, controversies and future perspectives from a neuropathological and clinical standpoint
- 2020
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In: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 46:2, s. 89-110
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Research review (peer-reviewed)abstract
- Neuroendocrine tumours of the adenohypophysis have traditionally been designated as pituitary adenomas to underline their usually indolent growth and lack of metastatic potential. However, they may demonstrate a huge spectrum of growth patterns and endocrine disturbances, some of them significantly affecting health and quality of life. To predict tumour growth, risk of postoperative recurrence and response to medical therapy in patients with pituitary neuroendocrine tumours is challenging. A thorough histopathological and immunohistochemical diagnostic work-up is an obligatory part of a multidisciplinary effort to precisely define the tumour type and assess prognostic and predictive factors on an individual basis. In this review, we have summarized the current status in the pathology in pituitary neuroendocrine tumours based on the selection of references from the PubMed database. We have presented possible diagnostic approaches according to the current pituitary cell lineage-based classification. The importance of recognizing histological subtypes with potentially aggressive behaviour and identification of prognostic and predictive tissue biomarkers have been highlighted. Controversies related to particular subtypes of pituitary tumours and a still limited prognostic impact of the current classification indicate the need for further refinement. Multidisciplinary approach including clinical, pathological and molecular genetic characterization will be essential for improved personalized therapy and the search for novel therapeutic targets in patients with pituitary neuroendocrine tumours.
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| 10. |
- Milosavljević, Filip, et al.
(author)
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The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
- 2023
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In: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 49:1
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Journal article (peer-reviewed)abstract
- Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
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