Alzheimer’s disease (AD) is characterized by the accumulation in the brain of intraneuronal aggregates of abnormally and hyperphosphorylated tau proteins and of extracellular deposits of amyloid-β surrounded by dystrophic neurites. Numerous experimental models have shown that tau pathology develops in the brain after intracerebral injection of brain homogenates or pathological tau [paired helical filaments (PHF)-tau)] from AD brains. Further investigations are however necessary to identify or exclude potential extracerebral routes of tau pathology transmission, e.g., through the intravascular route. In this study, we have analyzed the effect of intravenous injection of PHF-tau proteins from AD brains on the formation of tau and amyloid pathologies in the brain of wild-type (WT) mice and of 5XFAD mice (an amyloid model). We observed that 5XFAD mice with a disrupted blood–brain barrier showed increased plaque-associated astrogliosis, microgliosis, and increased deposits of Aβ40 and Aβ42 after intravenous injection of PHF-tau proteins. In addition, an increased phosphotau immunoreactivity was observed in plaque-associated dystrophic neurites. These results suggest that blood products contaminated by PHF-tau proteins could potentially induce an exacerbation of neuroinflammation and AD pathologies.

Background A negative potential is occasionally recorded in humans and animals with profound deafness during brainstem auditory evoked potential (BAER) tests if loud intensities are used. This acoustically evoked short latency negative response (ASNR) is hypothesized to be of saccular origin. The sensitivity to sound of vestibular end organs is also used to produce vestibular evoked myogenic potentials (VEMP), a test that evaluates vestibular function. The same saccular origin is accepted also for VEMP. Case presentation A neutered male white domestic short hair cat presented with profound deafness and an ASNR in the left ear during BAER test performed when he was 8 months old. BAER tracings were substantially unchanged at the age of 12 years, immediately before euthanasia that was requested by the owner for the presence of an unrelated neoplastic disorder. The cat underwent a complete post-mortem necropsy including histopathology of the middle and inner ears. Histopathologic results confirmed the presence of a cochleosaccular degeneration of the left ear while the cochlea and sacculus of the right ear and the utriculus and semicircular canals of both ears were histologically normal. Conclusions This case report describes the auditory and histopathologic findings of a cat that showed an ASNR during BAER test despite the presence of cochleosaccular deafness. These results confirm that a saccular origin for the ASNR in this case, and in general in cats and dogs with congenital deafness associated with white pigmentation, is improbable. The hypothesis that the sacculus is the vestibular end organ responsible for the generation of the ASNR and VEMP in humans comes mainly from animal studies. The findings in this report may change the clinical interpretation of the results of BAER and VEMP not only in companion animals, but in humans as well.

Human tauopathies are neurodegenerative diseases with accumulation of abnormally phosphorylated and aggregated tau proteins forming neurofibrillary tangles. We investigated the development of tau pathology in aged cat brains as a model of neurofibrillary tangle formation occurring spontaneously during aging. In 4 of 6 cats aged between 18 and 21 years, we found a somatodendritic accumulation of phosphorylated and aggregated tau in neurons and oligodendrocytes. Two of these 4 cats had no amyloid immunoreactivity. These tau inclusions were mainly composed of 4R tau isoforms and straight filaments and colocalized with the active form of the glycogen synthase kinase-3 (GSK3). Cat brains with a tau pathology showed a significant cortical atrophy and neuronal loss. We demonstrate in this study the presence of a tau pathology in aged cat brains that develop independently of amyloid deposits. The colocalization of the active form of the GSK3 with tau inclusions as observed in human tauopathies suggests that this kinase could be responsible for the abnormal tau phosphorylation observed in aged cat brains, representing a mechanism of tau pathology development shared between a naturally occurring tauopathy in aged cats and human tauopathies.

Event Abstract Back to Event Old cats : a naturally occuring model of tauopathy. Luc Poncelet1, Kunie Ando1, Cristina Vergara1, Emmanuel P. Gilissen1, Jean-Pierre Brion1 and Karelle Leroy1* 1 Free University of Brussels, Belgium Tauopathies comprise several neurodegenerative diseases such as Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia linked to chromosome 17 and Pick’s disease. These diseases have in common the presence of a cerebral lesion composed of abnormally phosphorylated and aggregated tau proteins forming filaments. In humans, 6 isoforms of tau proteins are expressed in the adult brain. These isoforms differ by the presence or absence of 1 or 2 inserts in the N terminal part of the protein (0N, 1N, 2N) and by the presence of 3 or 4 semi-repetitive microtubule binding domains in the C-terminal part of the protein (3R or 4R) (Isoforms called 0N3R, 1N3R, 2N3R, 0N4R, 1N4R, 2N4R). In cats, 5 isoforms are expressed in the brain of adult cats (0N3R, 2N3R, 0N4R, 1N4R, 2N4R). In Alzheimer’s disease, all the 6 isoforms of tau are found in neurofibrillary tangles of Alzheimer’s disease subjects whereas in progressive supranuclear palsy, corticobasal degeneration and some frontotemporal dementia, aggregated tau proteins are mainly composed of 4R isoforms. In Pick’s disease, the Pick bodies are mainly constituted of 3R tau. Previous studies have shown that phosphorylated tau proteins can form aggregates in mammalian species such as cats, goats or cynomolgus monkeys (Nelson et al. 1994 ; Oikawa et al., 2010 ; Chambers et al., 2015 ; Uchihara et al., 2016) but only in the presence of amyloid deposits in the cats (Chambers et al., 2015). In this study, we will show for the first time that a tau pathology could develop without the presence of amyloid deposits in old cats. We analyzed the brain of a cohort of cats between 2 and 21 years old for the presence of a tau pathology. Such a pathology was not found in cats younger than 18 years. In 3 among 5 cats aged between 18 and 21 years, we observed an accumulation of phosphorylated and aggregated tau in neuronal cell bodies and in oligodendrocytes. These tau aggregates were ubiquitin, PHF1, AT8, Gallyas, thioflavin, and thiazin red positive and were mainly composed of 4R tau isoforms. They were observed in the hippocampus and the adjacent cortex in these three cats, in the caudate putamen in two cats and even in the brain stem in one cat. Amyloid deposits were not detected in any of these 3 aged cats. The presence of hyperphosphorylated tau was confirmed by western blotting on the lysates from frontal cortex of these 3 cats. Phosphorylated tau are sarkosyl insoluble and forms straight filaments (observed by electron microscopy). In conclusion, we here document the existence of a naturally occurring 4R primary tauopathy in the feline species, associated with aging and independent of Aß deposits. This observation supports the hypothesis that tau and Aß pathologies develop initially independently in several mammalian species, in neurodegenerative diseases. References Chambers JK, Tokuda T, Uchida K, Ishii R, Tatebe H, Takahashi E, Tomiyama T, Une Y, Nakayama H. The domestic cat as a natural animal model of Alzheimer's disease. Acta Neuropathol Commun. 2015 Dec 10;3:78. Nelson PT, Greenberg SG, Saper CB. Neurofibrillary tangles in the cerebral cortex of sheep. Neurosci Lett. 1994 Mar 28;170(1):187-90. Oikawa N, Kimura N, Yanagisawa K. Alzheimer-type tau pathology in advanced aged nonhuman primate brains harboring substantial amyloid deposition. Brain Res. 2010 Feb 22;1315:137-49. Uchihara T, Endo K, Kondo H, Okabayashi S, Shimozawa N, Yasutomi Y, Adachi E, Kimura N. Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX. Acta Neuropathol Commun. 2016 Nov 14;4(1):118. Keywords: Tauopathy, tau, cat, Alzheimer, progressive supra nuclear palsy, Amyloid, Neurofibrillary Tangles, Old cats Conference: Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018. Presentation Type: e-posters Topic: NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE Citation: Poncelet L, Ando K, Vergara C, Gilissen EP, Brion J and Leroy K (2019). Old cats : a naturally occuring model of tauopathy.. Front. Neurosci. Conference Abstract: Belgian Brain Congress 2018 — Belgian Brain Council. doi: 10.3389/conf.fnins.2018.95.00007 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 08 Aug 2018; Published Online: 17 Jan 2019. * Correspondence: Prof. Karelle Leroy, Free University of Brussels, Brussels, Belgium, kleroy@ulb.ac.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Luc Poncelet Kunie Ando Cristina Vergara Emmanuel P Gilissen Jean-Pierre Brion Karelle Leroy Google Luc Poncelet Kunie Ando Cristina Vergara Emmanuel P Gilissen Jean-Pierre Brion Karelle Leroy Google Scholar Luc Poncelet Kunie Ando Cristina Vergara Emmanuel P Gilissen Jean-Pierre Brion Karelle Leroy PubMed Luc Poncelet Kunie Ando Cristina Vergara Emmanuel P Gilissen Jean-Pierre Brion Karelle Leroy Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The osmotic demyelination syndrome (ODS) is a non‐primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo , we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post‐correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post‐correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood–brain barrier (BBB) leakages. Expression levels of IL‐1β, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post‐correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS.

Background: Perinatal infections with feline panleukopenia virus (FPV) have long been known to be associated with cerebellar hypoplasia in kittens due to productive infection of dividing neuroblasts. FPV, like other parvoviruses, requires dividing cells to replicate which explains the usual tropism of the virus for the digestive tract, lymphoid tissues and bone marrow in older animals.Results: In this study, the necropsy and histopathological analyses of a series of 28 cats which died from parvovirus infection in 2013 were performed. Infections were confirmed by real time PCR and immunohistochemistry in several organs. Strikingly, while none of these cats showed cerebellar atrophy or cerebellar positive immunostaining, some of them, including one adult, showed a bright positive immunostaining for viral antigens in cerebral neurons (diencephalon). Furthermore, infected neurons were negative by immunostaining for p27(Kip1), a cell cycle regulatory protein, while neighboring, uninfected, neurons were positive, suggesting a possible re-entry of infected neurons into the mitotic cycle. Next-Generation Sequencing and PCR analyses showed that the virus infecting cat brains was FPV and presented a unique substitution in NS1 protein sequence. Given the role played by this protein in the control of cell cycle and apoptosis in other parvoviral species, it is tempting to hypothesize that a cause-to-effect between this NS1 mutation and the capacity of this FPV strain to infect neurons in adult cats might exist.Conclusions: This study provides the first evidence of infection of cerebral neurons by feline panleukopenia virus in cats, including an adult. A possible re-entry into the cell cycle by infected neurons has been observed. A mutation in the NS1 protein sequence of the FPV strain involved could be related to its unusual cellular tropism. Further research is needed to clarify this point.

Lipofuscin pigment accumulation is among the most prominent markers of cellular aging in postmitotic cells. The formation of lipofuscin is related to oxidative enzymatic activity and free radical-induced lipid peroxidation. In various mammals such as rat, dog, macaque as well as in cheirogaleid primates, most of the large neurons, such as cerebellar Purkinje cells and neocortical pyramidal cells, show heavy lipofuscin accumulation in adulthood. In contrast, a well-known yet poorly studied feature of the aging human brain is that although lipofuscin accumulation is most marked in large neurons of the cerebral cortex, the large neurons of the cerebellar cortex—the Purkinje cells—appear to remain free of lipofuscin accumulation. It is however, not known whether this characteristic of human Purkinje cells is shared with other primates or other mammals. This study reports results from histological observation of Purkinje cells in humans, non-human primates, and other mammals. Procedures include histochemistry, immunocytochemistry, and fluorescence microscopy. Abundant lipofuscin deposition was observed in Purkinje cells of all the species we examined except Homo sapiens (including Alzheimer’s disease cases) and Pan troglodytes . In contrast, lipofuscin deposition was observed in neurons of the dentate nucleus. Our findings suggest that when compared with other primates, Purkinje cells in chimpanzees and humans might share a common aging pattern that involves mechanisms for neuroprotection. This observation is important when considering animal models of aging.

The cell cycle-associated neuronal death hypothesis, which has been proposed as a common mechanism for most neurodegenerative diseases, is notably supported by evidencing cell cycle effectors in neurons. However, in naturally occurring nervous system diseases, these markers are not expressed in neuron nuclei but in cytoplasmic compartments. In other respects, the Feline Panleukopenia Virus (FPV) is able to complete its cycle in mature brain neurons in the feline species. As a parvovirus, the FPV is strictly dependent on its host cell reaching the cell cycle S phase to start its multiplication. In this retrospective study on the whole brain of 12 cats with naturally-occurring, FPV-associated cerebellar atrophy, VP2 capsid protein expression was detected by immunostaining not only in some brain neuronal nuclei but also in neuronal cytoplasm in 2 cats, suggesting that viral mRNA translation was still occurring. In these cats, double immunostainings demonstrated the expression of cell cycle S phase markers cyclin A, cdk2 and PCNA in neuronal nuclei. Parvoviruses are able to maintain their host cells in S phase by triggering the DNA damage response. S139 phospho H2A1, a key player in the cell cycle arrest, was detected in some neuronal nuclei, supporting that infected neurons were also blocked into the S phase. PCR studies did not support a co-infection with an adeno or herpes virus. ERK1/2 nuclear accumulation was observed in some neurons suggesting that the ERK signaling pathway might be involved as a mechanism driving these neurons far into the cell cycle.

Several neurodegenerative diseases are characterized by both cognitive and motor deficits associated with accumulation of tau aggregates in brain, brainstem, and spinal cord. The Tg30 murine tauopathy model expresses a human tau protein bearing two frontotemporal dementia with Parkinsonism linked to chromosome 17 pathogenic mutations and develops a severe motor deficit and tau aggregates in brain and spinal cord. To investigate the origin of this motor deficit, we analyzed the age-dependent innervation status of the neuromuscular junctions and mutant tau expression in Tg30 mice. The human transgenic tau was detected from postnatal day 7 onward in motoneurons, axons in the sciatic nerve, and axon terminals of the neuromuscular junctions. The development and maturation of neuromuscular junctions were not disrupted in Tg30 mice, but their maintenance was disturbed in adult Tg30 mice, resulting in a progressive and severe muscle denervation. This muscle denervation was associated with early electrophysiological signs of muscle spontaneous activities and histological signs of muscle degeneration. Early loss of synaptic vesicles in axon terminals preceding motor deficits, accumulation of Gallyas-positive aggregates, and cathepsin-positive vesicular clusters in axons in the sciatic nerve suggest that this denervation results from disturbances of axonal transport. This physiopathological mechanism might be responsible for motor signs observed in some human tauopathies, and for synaptic dysfunction resulting from alterations at the presynaptic level in these diseases.

Canine angiostrongylosis is considered as an emergent disease in Europe and Canada. A fatal case of Angiostrongylus vasorum infection is described in a four and a half month old puppy born in Belgium. The dog was presented with marked neurological disorders, body weight loss, a profound weakness and mild respiratory signs. The dog was given antibiotics and mucolytic compounds with very little improvement and consequently was referred to a specialist for additional examinations. As the general condition of the dog was rapidly declining, the animal was euthanized shortly after on its owners' request and a necropsy was carried out. Extensive gross pulmonary lesions were observed and histopathological examination revealed the presence of numerous larvae with morphology compatible with A. vasorum. Larvae were also found in the product of a bronchoalveolar lavage but fecal material was not examined. The presence of A. vasorum circulating serum antigen was demonstrated through ELISA; additionally an A. vasorum specific PCR was performed on brain material and yielded a positive result. This case confirms that the clinical diagnosis of canine angiostrongylosis can be very challenging especially when respiratory signs are absent or very mild such in the present case. This is the first reported case of canine angiostrongylosis in Belgium.

Cerebellar cortices from feline fetuses with estimated gestational ages of 40-66days and from kittens aged 2days to 2months, all negative for feline panleukopenia virus (FPV) infection, were analysed for expression of the transferrin receptor 1 (TrFR1), proliferating cell nuclear antigen (PCNA), p27(Kip1) and calbindin. TrFR1, the receptor used by FPV to enter target cells, was expressed in capillary endothelial cells in the cerebellum at all fetal stages investigated and in Purkinje cells of a 3-week-old kitten, but not in the neuroblasts in the external granule layer (EGL). PCNA was expressed in cells of the superficial layer of the EGL. The cyclin-dependent kinase inhibitor p27(Kip1) was expressed in cells of the deep layer of the EGL. Purkinje cells expressed calbindin from the earliest fetal stage investigated. Co-expression of PCNA and calbindin could not be demonstrated, indicating that feline Purkinje cells are post-mitotic from at least 40days gestation.

Parvoviruses depend on initiation of host cell division for their replication. Undefined parvoviral proteins have been detected in Purkinje cells of the cerebellum after experimental feline panleukopenia virus (FPV) infection of neonatal kittens and in naturally occurring cases of feline cerebellar hypoplasia. In this study, a parvoviral protein in the nucleus of Purkinje cells of kittens with cerebellar hypoplasia was shown by immunoprecipitation to be the FPV viral capsid protein VP2. In PCR-confirmed, FPV-associated feline cerebellar hypoplasia, expression of the FPV VP2 protein was demonstrated by immunohistochemistry in Purkinje cell nuclei in 4/10 cases and expression of the FPV non-structural protein NS1 was demonstrated in Purkinje cell nuclei in 5/10 cases. Increased nuclear ERK1 expression was observed in several Purkinje cells in 1/10 kittens. No expression of the G1 and S mitotic phase marker proliferating cell nuclear antigen (PCNA) was evident in Purkinje cell nuclei. These results support the hypothesis that FPV is able to proceed far into its replication cycle in post-mitotic Purkinje cells.

SUDDEN-ONSET paraplegia with signs indicating a spinal cord lesion close to the thoracolumbar junction is a frequent presentation in dogs. If there is no history of trauma, fibrocartilaginous thromboembolism and intervertebral disc extrusion are the most likely causes, and these can be differentiated by imaging. One case of intradural disc herniation in a dog has been reported; this animal was euthanased (Liptak and others 2002). In human beings, intradural disc herniation is a rare condition, comprising 0.27 per cent of all disc herniations (Han and others 2009). This short communication describes a case of intradural disc herniation in a dog and its successful surgical treatment. A 13-year-old male miniature schnauzer was presented with a history of sudden-onset paraplegia of two days' duration with no observed trauma or unusual vertebral column stress. The dog was paraplegic, with subtle voluntary movement of the left pelvic limb; it did not exhibit back pain on palpation. Muscle tone and stretch reflexes were increased in …