Browsing by Subject "neurodegeneration"
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(2022)Inclusion bodies are intracellular limited aggregates that consist of subcellular components, such as proteins, that have folded incorrectly, accumulated, and not been eliminated by cells protective systems. Neuronal cytoplasmic inclusion bodies are formed in many human neurodegenerative diseases but have also been found in some canine neurodegenerative diseases. Malfunction of protein degradation systems has been linked to formation of inclusion bodies but the underlying purpose behind inclusion body formation is still often unknown. Lagotto Romagnolo (LR) is an old Italian dog breed. Several neurological diseases, such as benign familial juvenile epilepsy and cerebellar cortical abiotrophy, are known to occur among LR dogs. Eosinophilic neuronal cytoplasmic inclusion bodies have been discovered in brain samples of LR dogs with benign familial juvenile epilepsy and in LRs without clinical signs of disease. This licentiate thesis consists of a literature review and a histological study. The literature review introduces neuronal inclusion bodies and their known contents in general, as well as human and canine diseases linked to these inclusion bodies along with cellular processes that might be linked to the formation of inclusions. The most common staining methods used for neuronal inclusion bodies are also presented briefly. The study is a descriptive, retrospective study aiming to define the content of neuronal cytoplasmic inclusion bodies of LR dogs. The study material consisted of formalin-fixed, paraffin-embedded brain samples from four LR dogs that underwent autopsy at Section for Veterinary Pathology, University of Helsinki, from 2012 to 2018. One female dog with and three female dogs without neurological signs, all with a finding of intraneuronal cytoplasmic inclusions in the brain sections stained with hematoxylin-eosin-stain, were chosen for further stainings. The geniculate nuclei brain samples were stained histochemically for glycoproteins, lipoproteins, basic amino acids, and fibrin. Immunohistochemical stains used were ubiquitin, a-synuclein, β-amyloid, p62, LC3 and 1C2. The inclusions stained positively with Mallory phosphotungstic acid hematoxylin staining (PTAH) in all tested samples. PTAH is a histochemical stain with a high affinity to basic amino acids lysine, arginine, and histidine. Neuronal inclusion bodies that are positive on PTAH have been found as spontaneous age-related lesions in laboratory mice. In electron microscopy, the inclusion material was electron dense and finely granular with some small vesicular profiles without a limiting membrane. In conclusion, the neuronal inclusion bodies in geniculate nuclei of LR dogs in this study contain basic amino acids and not carbohydrates, lipids, or fibrinous material. The inclusion bodies are, however, not targeted for degradation as no p62, LC3 or ubiquitin signal was detected. Aggregation of a-synuclein or β-amyloid were also not detected within the inclusion.
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(2021)Mild traumatic brain injury (TBI) is defined as an injury that disrupts the normal functioning of the brain and is the result of external force to the head. It is the most common type of traumatic head injury, and it is common especially in contact sports and within military personnel. Mild TBI typically causes no clear structural changes to the head, but it can induce persistent clinical symptoms, as well as microscopic pathological changes to the brain that may eventually lead to neurodegeneration and increase the risk for several diseases. Mild TBI is a risk factor for several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy. The primary objective of this study was to develop a repetitive mild TBI mouse model for future research purposes in the field of head trauma and neurodegeneration. The injury was induced as a closed head injury with an electromagnetic impactor. Literature and pilot experiments were used to define the parameters of the impactor required to induce a brain injury of desired severity. The characterization criteria of the mild TBI model considered the criteria used to define human mild TBI, as well as long term effects often reported after repetitive mild TBI: neurodegeneration as tau protein related pathology, neuroinflammation, and memory deficits. The secondary objective of this study was to tentatively test a prolyl oligopeptidase (PREP) inhibitor on the behavioral and histological effects of mild TBI. The functioning of the mild TBI model was studied by histopathological and behavioral assessments. After baseline behavioral assessment and repetitive (1 injury every 24 hours altogether 5 times) mild TBI inductions, the mice were monitored for approximately 3 months, during which several rounds of behavioral tests were performed. Barnes maze and novel object recognition tests were used to assess memory functions, and locomotor activity test was used to assess general locomotor activity. After euthanasia, brain histopathology was performed to study the amount of tau protein and the level of neuroinflammation. Due to the low number of animals in the study, the results are directional and need to be confirmed in subsequent studies. The histopathology showed greater amount of neuroinflammation and tau protein in the brains of injured mice, but statistical evaluations could not be made. Memory functions were slightly worse in the injured mice compared to controls, but significance of the results is unclear. Locomotor activity was not influenced by the mild TBIs. PREP inhibition treatment increased the locomotor activity of the mice, but the significance is unclear. The mild TBI model seems promising and the characterization criteria were partially met. The results of the study need to be verified in subsequent studies with a greater amount of animals. The model developed here can be used to study the involvement of head trauma in neurodegeneration, as well as treatment alternatives to changes caused by mild TBIs. As there currently are no curative treatments to neurodegenerative diseases, research regarding neurodegeneration and its risk factors is highly important.
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(2021)Mild traumatic brain injury (TBI) is defined as an injury that disrupts the normal functioning of the brain and is the result of external force to the head. It is the most common type of traumatic head injury, and it is common especially in contact sports and within military personnel. Mild TBI typically causes no clear structural changes to the head, but it can induce persistent clinical symptoms, as well as microscopic pathological changes to the brain that may eventually lead to neurodegeneration and increase the risk for several diseases. Mild TBI is a risk factor for several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy. The primary objective of this study was to develop a repetitive mild TBI mouse model for future research purposes in the field of head trauma and neurodegeneration. The injury was induced as a closed head injury with an electromagnetic impactor. Literature and pilot experiments were used to define the parameters of the impactor required to induce a brain injury of desired severity. The characterization criteria of the mild TBI model considered the criteria used to define human mild TBI, as well as long term effects often reported after repetitive mild TBI: neurodegeneration as tau protein related pathology, neuroinflammation, and memory deficits. The secondary objective of this study was to tentatively test a prolyl oligopeptidase (PREP) inhibitor on the behavioral and histological effects of mild TBI. The functioning of the mild TBI model was studied by histopathological and behavioral assessments. After baseline behavioral assessment and repetitive (1 injury every 24 hours altogether 5 times) mild TBI inductions, the mice were monitored for approximately 3 months, during which several rounds of behavioral tests were performed. Barnes maze and novel object recognition tests were used to assess memory functions, and locomotor activity test was used to assess general locomotor activity. After euthanasia, brain histopathology was performed to study the amount of tau protein and the level of neuroinflammation. Due to the low number of animals in the study, the results are directional and need to be confirmed in subsequent studies. The histopathology showed greater amount of neuroinflammation and tau protein in the brains of injured mice, but statistical evaluations could not be made. Memory functions were slightly worse in the injured mice compared to controls, but significance of the results is unclear. Locomotor activity was not influenced by the mild TBIs. PREP inhibition treatment increased the locomotor activity of the mice, but the significance is unclear. The mild TBI model seems promising and the characterization criteria were partially met. The results of the study need to be verified in subsequent studies with a greater amount of animals. The model developed here can be used to study the involvement of head trauma in neurodegeneration, as well as treatment alternatives to changes caused by mild TBIs. As there currently are no curative treatments to neurodegenerative diseases, research regarding neurodegeneration and its risk factors is highly important.
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(2022)Parkinsonin tauti on maailman yleisin hermorappeumaa aiheuttava liikehäiriösairaus. Taudin ilmaantuvuus- ja esiintyvyysluvut ovat jatkuvassa nousussa, mitä väestön ikääntyminen ei yksin selitä. Taudin patologisia löydöksiä ovat alfasynukleiinin kertyminen ja vääränlaisesta laskostumisesta johtuva aggregaatio, Lewy neuriittien ja kappaleiden kertyminen sekä dopaminergisten hermosolujen solukato mustatumakkeesta. Taudin pidemmälle edenneille vaiheille on tyypillistä vaikea toimintakyvyttömyys ja elinajanodotteen lasku. Nykyiset hoitomuodot niin Parkinsonin taudille, kuin muillekin hermorappeumasairauksille ovat ainoastaan oireita lievittäviä. Onnistuneeseen lääkekehitykseen vaaditaan parannusta eläinmallien validiteetin jokaisella alatasolla. Parkinsonin taudin käytössä olevissa prekliinisissä eläinmalleissa on huono ilmivaliditeetti monien potilailla tehtyjen patologisten löydösten puuttuessa. Tässä tutkielmassa esitän uudenlaisen SynFib rottamallin Parkinsonin tautiin. Eksogeenisesti valmistettuja ihmisen alfasynukleiinifibrillejä injisoitiin yhdessä alfasynukleiinia ekspressoivien virusvektoreiden kanssa mustatumakkeeseen. Injektio aiheutti intensiivisen ja etenevän alfasynukleiinista johtuvan patologian ja merkittävän dopaminergisen soluvaurion. Taudin etenemistä seurattiin pitkittäistutkimuksessa positroniemissiotomografialla ja toiminnallisia puutteita arvioitiin synapsitiheydessä, inflammaatiossa ja dopaminergisessa järjestelmässä 16 viikon ajan. Havaitsin aivokudoksen tulehduksen ja dopaminergisen ipsilateraalisen soluvaurion lisääntyneen merkittävästi. Kahden viikon kohdalla synapsitiheys oli merkittävästi vähentynyt ipsilateraalisesti ja taudin leviäminen kontralateraaliselle puolelle oli alkanut.
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(2022)Parkinsonin tauti on maailman yleisin hermorappeumaa aiheuttava liikehäiriösairaus. Taudin ilmaantuvuus- ja esiintyvyysluvut ovat jatkuvassa nousussa, mitä väestön ikääntyminen ei yksin selitä. Taudin patologisia löydöksiä ovat alfasynukleiinin kertyminen ja vääränlaisesta laskostumisesta johtuva aggregaatio, Lewy neuriittien ja kappaleiden kertyminen sekä dopaminergisten hermosolujen solukato mustatumakkeesta. Taudin pidemmälle edenneille vaiheille on tyypillistä vaikea toimintakyvyttömyys ja elinajanodotteen lasku. Nykyiset hoitomuodot niin Parkinsonin taudille, kuin muillekin hermorappeumasairauksille ovat ainoastaan oireita lievittäviä. Onnistuneeseen lääkekehitykseen vaaditaan parannusta eläinmallien validiteetin jokaisella alatasolla. Parkinsonin taudin käytössä olevissa prekliinisissä eläinmalleissa on huono ilmivaliditeetti monien potilailla tehtyjen patologisten löydösten puuttuessa. Tässä tutkielmassa esitän uudenlaisen SynFib rottamallin Parkinsonin tautiin. Eksogeenisesti valmistettuja ihmisen alfasynukleiinifibrillejä injisoitiin yhdessä alfasynukleiinia ekspressoivien virusvektoreiden kanssa mustatumakkeeseen. Injektio aiheutti intensiivisen ja etenevän alfasynukleiinista johtuvan patologian ja merkittävän dopaminergisen soluvaurion. Taudin etenemistä seurattiin pitkittäistutkimuksessa positroniemissiotomografialla ja toiminnallisia puutteita arvioitiin synapsitiheydessä, inflammaatiossa ja dopaminergisessa järjestelmässä 16 viikon ajan. Havaitsin aivokudoksen tulehduksen ja dopaminergisen ipsilateraalisen soluvaurion lisääntyneen merkittävästi. Kahden viikon kohdalla synapsitiheys oli merkittävästi vähentynyt ipsilateraalisesti ja taudin leviäminen kontralateraaliselle puolelle oli alkanut.
Now showing items 1-5 of 5