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Calbindin immunohistochemistry in A β PP/PS1 mouse cerebellum aged 18/20 months shows enlarged Purkinje cell axons in the white matter (a, arrow), axonal spheroids: torpedoes (b, arrows), and hypertrophic infra-ganglionic plexuses (c, arrow). Focal loss of Purkinje cells and corresponding arbors (d and insert) is observed in A β PP/PS1 mice. Electron microscopy shows a branch of a Purkinje cell dendrite (e, arrows) filled with large mitochondria and occasional electron-dense mitochondria (arrowhead) in the vicinity of dystrophic neurite (PF). Double-labeling immunofluorescence for calbindin (red) and A  (green) shows A  plaques in the molecular layer, some of them displacing the arbors of Purkinje cells, but apparently not producing dystrophic neurites (f, g). Nuclei are stained with Draq5 (blue). Electron microscopy shows a degenerating Purkinje cell with dark nucleus and cytoplasm, and enlarged cisternae of the endoplasmic reticulum, together with increased lipofuscin deposition (h). ML = molecular layer, Pc = Purkinje cell layer, IGL = granule cell layer, WM = white matter.
Source publication
Cerebellar amyloid-β (Aβ) deposition in the form of neuritic plaques and Purkinje cell loss are common in certain pedigrees of familial Alzheimer's disease (FAD) mainly linked to PS1 mutations. AβPP/PS1 transgenic mice, here used as a model of FAD, show a few Aβ plaques in the molecular layer of the cerebellum at 6 months, and which increase in num...
Contexts in source publication
Context 1
... immunohistochemistry revealed various alterations of Purkinje cells, including the presence of enlarged axons (Fig. 5a), axonal spheroids (Fig. 5b), and hypertrophic infra-ganglionic plexuses (Fig. 5c). In addition, some convolutions were devoid of Purkinje cells (Fig. 5d). Cell counting revealed that the linear cell density of Purkinje cells was reduced by 18% and 25% in transgenic mice in comparison with WT ani- mals at the age of 12 and 18/20 ...
Context 2
... immunohistochemistry revealed various alterations of Purkinje cells, including the presence of enlarged axons (Fig. 5a), axonal spheroids (Fig. 5b), and hypertrophic infra-ganglionic plexuses (Fig. 5c). In addition, some convolutions were devoid of Purkinje cells (Fig. 5d). Cell counting revealed that the linear cell density of Purkinje cells was reduced by 18% and 25% in transgenic mice in comparison with WT ani- mals at the age of 12 and 18/20 months, respectively (p < 0.05 and ...
Context 3
... immunohistochemistry revealed various alterations of Purkinje cells, including the presence of enlarged axons (Fig. 5a), axonal spheroids (Fig. 5b), and hypertrophic infra-ganglionic plexuses (Fig. 5c). In addition, some convolutions were devoid of Purkinje cells (Fig. 5d). Cell counting revealed that the linear cell density of Purkinje cells was reduced by 18% and 25% in transgenic mice in comparison with WT ani- mals at the age of 12 and 18/20 months, respectively (p < 0.05 and p < 0.001, at the ages of 12 months and 18/20 ...
Context 4
... immunohistochemistry revealed various alterations of Purkinje cells, including the presence of enlarged axons (Fig. 5a), axonal spheroids (Fig. 5b), and hypertrophic infra-ganglionic plexuses (Fig. 5c). In addition, some convolutions were devoid of Purkinje cells (Fig. 5d). Cell counting revealed that the linear cell density of Purkinje cells was reduced by 18% and 25% in transgenic mice in comparison with WT ani- mals at the age of 12 and 18/20 months, respectively (p < 0.05 and p < 0.001, at the ages of 12 months and 18/20 ...
Context 5
... microscopic examination of the molecular layer revealed the presence of large mitochon- dria in dendrites and small branches of Purkinje cells, accompanied by occasional dark mitochon- dria at the ages of 12 and 18/20 months (Fig. 5e). Dendritic arbors of Purkinje cells were distorted around the amyloid deposits, as shown by double- labeling immunofluorescence to calbindin and A, and confocal microscopy (Fig. 5f, g). No calbindin- immunoreactive dystrophic processes were evidenced with double-labeling immunofluorescence and confo- cal ...
Context 6
... presence of large mitochon- dria in dendrites and small branches of Purkinje cells, accompanied by occasional dark mitochon- dria at the ages of 12 and 18/20 months (Fig. 5e). Dendritic arbors of Purkinje cells were distorted around the amyloid deposits, as shown by double- labeling immunofluorescence to calbindin and A, and confocal microscopy (Fig. 5f, g). No calbindin- immunoreactive dystrophic processes were evidenced with double-labeling immunofluorescence and confo- cal ...
Citations
... However, a growing literature has shown cerebellar involvement in MCI and AD in the form of GM and WM atrophy. 34,35,36,5,2 Our findings form part of the growing body of work indicating functional connectivity differences in AD 37,38,39,40,41 and relationships with behavioral task performance, including emerging work on cerebellar networks. 26 Here, we found that the AD group displayed a mix of higher and lower FC in both vDN and dDN networks when compared to CN individuals. ...
Recent research has implicated the cerebellum in Alzheimers disease (AD), and cerebro- cerebellar network connectivity is emerging as a possible contributor to symptom severity. The cerebellar dentate nucleus (DN) has parallel motor and non-motor sub-regions that project to motor and frontal regions of the cerebral cortex, respectively. These distinct dentato-cortical networks have been delineated in the non-human primate and human brain. Importantly, cerebellar regions prone to atrophy in AD are functionally connected to atrophied regions of the cerebral cortex, suggesting that dysfunction perhaps occurs at a network level. Investigating functional connectivity (FC) alterations of the DN is a crucial step in understanding the cerebellum in AD and in mild cognitive impairment (MCI). Inclusion of this latter group stands to provide insights into cerebellar contributions prior to diagnosis of AD. The present study investigated FC differences in dorsal (dDN) and ventral (vDN) DN networks in MCI and AD relative to cognitively normal participants (CN) and relationships between FC and behavior. Our results showed patterns indicating both higher and lower functional connectivity in both dDN and vDN in AD compared to CN. However, connectivity in the AD group was lower when compared to MCI. We argue that these findings suggest that the patterns of higher FC in AD may act as a compensatory mechanism. Additionally, we found associations between the individual networks and behavior. There were significant interactions between dDN connectivity and motor symptoms. However, both DN seeds were associated with cognitive task performance. Together, these results indicate that cerebellar DN networks are impacted in AD, and this may impact behavior. In concert with the growing body of literature implicating the cerebellum in AD, our work further underscores the importance of investigations of this region. We speculate that much like in psychiatric diseases such as schizophrenia, cerebellar dysfunction results in negative impacts on thought and the organization therein. Further, this is consistent with recent arguments that the cerebellum provides crucial scaffolding for cognitive function in aging. Together, our findings stand to inform future clinical work in the diagnosis and understanding of this disease.
... Neurofibrillary tangles are absent in this model. These mice also display progressive loss of motor coordination in wire hanging, rotarod, and balance beam tests [28,29]. However, spatiotemporal parameters of gait have yet to be characterized in this model. ...
... We have previously shown that vitamin D deficiency did not cause any changes in weight or body composition in APPswe/PS1dE9 mice visible at 15 months of age [30]; however, it is possible that vitamin D deficiency affected gait through neurological processes. Another study in APPswe/PS1dE9 mice found progressive development of morphological abnormalities in the cerebellar cortex resulting in decreased performance in wire-hanging and rotarod tests [28]. As vitamin D deficiency is known to increase the risk for ADassociated cognitive decline [12], it is possible that vitamin D deficiency in the present study accelerated the development of cerebellar abnormalities, leading to the observed increase in hind stride width compared to mice fed a control diet. ...
... With respect to the gait parameters for which an effect of age was not observed in this study, the discrepancy with human studies may be due to the timeline of the current study rather than the ability of APPswe/PS1dE9 mice to model spatiotemporal gait. In previous studies of APPswe/PS1dE9 mice ranging from 3 to 12 months old, performance on wirehanging, rotarod, and balance beam tests were found to worsen with age [28,29]. It was therefore expected that spatiotemporal measures of gait in this model would also worsen with age and that any changes would be observable within our study's timeline (6 to 15 months of age). ...
Background:
Altered gait is a frequent feature of Alzheimer's disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-β and glutamate toxicity, suggesting this combination may mitigate altered gait in AD.
Objective:
Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice.
Methods:
Male APPswe/PS1dE9 mice were split into four groups (n = 14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups started a vitamin D-deficient diet at month 6. One group remained on this deficient diet for the rest of the study. At month 9, the other two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait was assessed using CatWalk at months 6, 9, 12, and 15.
Results:
Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p < 0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p < 0.01), while mice treated with memantine and vitamin D did not (p = 0.21).
Conclusion:
Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD.
... Moreover, there were age-related changes in the morphology of amyloid plaques in the brain of APP/PS1 mice, with small compact, large diffuse, and diffuse and dense-core plaques at 4, 9 and 17 months of age respectively. These findings are consistent with earlier reports showing age-related amyloid accumulation in the brain of APP/PS1 mice (Garcia-Alloza et al., 2006;Hoxha et al., 2018;Kuwabara et al., 2014;Lomoio et al., 2012;Ruan et al., 2009). ...
Amyloid-beta (Aβ) cleaved from amyloid precursor protein (APP) has been proposed to play a central and causative role in the aetiology of Alzheimer’s disease (AD). APPswe/PSEN1dE9 (APP/PS1) transgenic mice display chronic Aβ accumulation and deposition in the brain. L-arginine is a semi-essential amino acid with a number of bioactive metabolites, and altered arginine metabolism has been implicated in the pathogenesis and/or the development of AD. This study systematically investigated how arginine metabolic profiles changed in the frontal cortex, hippocampus, parahippocampal region and cerebellum of male APP/PS1 mice at 4, 9 and 17 months of age relative to their sex- and age-matched wildtype controls. Immunohistochemistry demonstrated age-related Aβ deposition in the brain. High-performance liquid chromatography and mass spectrometry revealed age-related increases in glutamine, spermidine and spermine in APP/PS1 mice in a region-specific manner. Notably, genotype-related increases in spermine were found in the frontal cortex at the 9-month age point and in the frontal cortex, hippocampus and parahippocampal region at 17 months of age. Given the existing literature indicating the role of polyamines (spermine in particular) in modulating the aggregation and toxicity of Aβ oligomers, increased spermidine and spermine levels in APP/PS1 mice may be a neuroprotective mechanism to combat Aβ toxicity. Future research is required to better understand the functional significance of these changes.
... However, in the cerebellum, Aβ deposits are detected only after 12 months, when these animals begin developing motor deficits. An increase in astrocytic glial reactivity is observed in the cerebellum after 18 months [254], whereas in the hippocampus of these animals, glial reactivity occurs after 6 months [255]. It is already accepted that astrocytes play an important role in AD, such as in Aβ production and metabolization and the production of inflammatory mediators and reactive oxygen species [256][257][258]. ...
Astrocytes, initially described as merely support cells, are now known as a heterogeneous population of cells actively involved in a variety of biological functions such as: neuronal migration and differentiation; regulation of cerebral blood flow; metabolic control of extracellular potassium concentration; and modulation of synapse formation and elimination; among others. Cerebellar glial cells have been shown to play a significant role in proliferation, differentiation, migration, and synaptogenesis. However, less evidence is available about the role of neuron-astrocyte interactions during cerebellar development and their impact on diseases of the cerebellum. In this review, we will focus on the mechanisms underlying cellular interactions, specifically neuron-astrocyte interactions, during cerebellar development, function, and disease. We will discuss how cerebellar glia, astrocytes, and Bergmann glia play a fundamental role in several steps of cerebellar development, such as granule cell migration, axonal growth, neuronal differentiation, and synapse formation, and in diseases associated with the cerebellum. We will focus on how astrocytes and thyroid hormones impact cerebellar development. Furthermore, we will provide evidence of how growth factors secreted by glial cells, such as epidermal growth factor and transforming growth factors, control cerebellar organogenesis. Finally, we will argue that glia are a key mediator of cerebellar development and that identification of molecules and pathways involved in neuron-glia interactions may contribute to a better understanding of cerebellar development and associated disorders.
... Similar anatomical and temporal patterns of alterations develop in the cerebellum of transgenic mice models of FAD. For example, APPswe/PSEN1dE9 mice show few diffuse Aβ deposits in the molecular layer at 6 months of age; the number of cerebellar deposits increases with disease progression and at higher rate in females vs. males (Lomoio et al., 2012;Kuwabara et al., 2014). At 18/20 months of age, the Aβ plaques appear surrounded by dystrophic neurites, microglia and astrocytes; focal loss of PCs and degeneration of parallel fibers (PFs) have been also observed. ...
The role of the cerebellum in Alzheimer’s disease (AD) has been neglected for a long time. Recent studies carried out using transgenic mouse models have demonstrated that amyloid-β (Aβ) is deposited in the cerebellum and affects synaptic transmission and plasticity, sometimes before plaque formation. A wide variability of motor phenotype has been observed in the different murine models of AD, without a consistent correlation with the extent of cerebellar histopathological changes or with cognitive deficits. The loss of noradrenergic drive may contribute to the impairment of cerebellar synaptic function and motor learning observed in these mice. Furthermore, cerebellar neurons, particularly granule cells, have been used as in vitro model of Aβ-induced neuronal damage. An unexpected conclusion is that the cerebellum, for a long time thought to be somehow protected from AD pathology, is actually considered as a region vulnerable to Aβ toxic damage, even at the early stage of the disease, with consequences on motor performance.
... We also used murine models of -amyloidopathy, tauopathy, AD, and HD, as well as mice expressing human prion protein inoculated with CJD brain homogenates to test putative agents directed to altered metabolic pathways identified in human studies [201][202][203][204][205]. Parallel experience with X-ALD mice was useful to test several therapeutic agents directed to specific targets in that model [206][207][208][209]. ...
The study of life and living organisms and the way in which these interact and organize to form social communities have been central to my career. I have been fascinated by biology, neurology, and neuropathology, but also by history, sociology, and art. Certain current historical, political, and social events, some occurring proximally but others affecting people in apparently distant places, have had an impact on me. Epicurus, Seneca, and Camus shared their philosophical positions which I learned from. Many scientists from various disciplines have been exciting sources of knowledge as well. I have created a world of hypothesis and experiments but I have also got carried away by serendipity following unexpected observations. It has not been an easy path; errors and wanderings are not uncommon, and opponents close to home much more abundant than one might imagine. Ambition, imagination, resilience, and endurance have been useful in moving ahead in response to setbacks. In the end, I have enjoyed my dedication to science and I am grateful to have glimpsed beauty in it. These are brief memories of a Spanish neuropathologist born and raised in Barcelona, EU.
... pathophysiology of the disease. Wild-type mice do not develop amyloid plaques as they age Lomoio et al., 2012), but the transgenic mouse models develop soluble (Xiong et al., 2011) and diffuse amyloid accumulations in early stages of the disease , and amyloid plaques increase as the mice age, mainly in Purkinje cell (Brock et al., 2008) and molecular layers of the cerebellum . Further, at advanced age, the mice also develop neuritic plaques containing tau. ...
The cerebellum has long been regarded as essential only for the coordination of voluntary motor activity and motor learning. Anatomical, clinical and neuroimaging studies have led to a paradigm shift in the understanding of the cerebellar role in nervous system function, demonstrating that the cerebellum appears integral also to the modulation of cognition and emotion. The search to understand the cerebellar contribution to cognitive processing has increased interest in exploring the role of the cerebellum in neurodegenerative and neuropsychiatric disorders. Principal among these is Alzheimer's disease. Here we review an already sizeable existing literature on the neuropathological, structural and functional neuroimaging studies of the cerebellum in Alzheimer's disease. We consider these observations in the light of the cognitive deficits that characterize Alzheimer's disease and in so doing we introduce a new perspective on its pathophysiology and manifestations. We propose an integrative hypothesis that there is a cerebellar contribution to the cognitive and neuropsychiatric deficits in Alzheimer's disease. We draw on the dysmetria of thought theory to suggest that this cerebellar component manifests as deficits in modulation of the neurobehavioural deficits. We provide suggestions for future studies to investigate this hypothesis and, ultimately, to establish a comprehensive, causal clinicopathological disease model.
... However, proper reproduction of neuronal loss in AD models has been the main hurdle for modeling. This feature is almost negligible in most of the APP-transgenic mice although it has been observed in some APP/PS1-transgenic models [48][49][50][51]. For instance, neuronal depletion has been described in 9-month-old 5xFAD mice, which contains five additive mutations causing A overproduction and accumulation already at 1.5 months [8]. ...
The main histopathological hallmarks of Alzheimer's disease (AD) are the extracellular deposition of neuritic amyloid plaques, composed of amyloid-β (Aβ) peptide, and the intracellular accumulation of neurofibrillary tangles, composed of hyperphosphorylated tau. Both traits are emulated in the 3xTg-AD mouse model. Because the relevance of this model in the bibliography and the main role of Aβ in neuronal impairment, here we have detailed the brain Aβ/AβPP distribution to subsequently quantify cellular density and intracellular burden for specific neuronal populations in the early stages of the disease. 6E10 immunoreactivity was evident in the deep layers of the cerebral cortex, in the pyramidal cell layer of the hippocampus, in the basolateral amygdala nucleus, and in the deep cerebellar nuclei macroneurons; whereas the specific neuronal populations with decreased cellular density were the large pyramidal neurons from the layers V-VI in the cerebral cortex, the pyramidal neurons from the CA2-3 region in the hippocampus, and the large neurons from the basolateral nucleus in the amygdala, apart from the already reported deep cerebellar nuclei. Interestingly, we found a strong correlation between intracellular Aβ/AβPP burden and cellular density in all these populations. In addition, behavioral testing showed the functional consequences of such a neuronal depletion. Concretely, anxious-like behavior is manifested in the corner and open-field tests, as well as cognitive functions shown to be impaired in the novel object recognition test and Morris water maze paradigm. To our knowledge, this is the first deep characterization of the specific neuronal populations affected in the 3xTg-AD mouse model.
... However, patients that carried PS1 mutations showed abundant deposits of A mainly localized in the Purkinje and molecular layers. The presence of A plaques in the molecular layer of the cerebellum in transgenic mice has been already described [25,36], confirming our results and those obtained in patients. ...
... In the APP/PS1 mice model, GFAP-positive cells appear usually surrounding A plaques, in the cortex and hippocampus [21]. Cerebellum A plaques have been described as being surrounded by microglia, astrocytes, and dystrophic neurites [36]. These authors described the presence of GFAP reaction surrounded A deposits in the ML. ...
Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer's disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach.
... Since 1999, at least 53 human research articles have been published demonstrating that besides its role in coordination of voluntary movement, gait, posture, speech and motor function, the cerebellum helps control cognitive functions that require precise timing and behavior [63][64][65][66][67]. It is also believed that cell loss in the cerebellum could be related to coordination deficits that often occur in mid-to-late stages of AD [67][68][69][70][71]. The present work was designed to increase understanding of the nature and degree to which a novel δ/γ PPAR agonist might be beneficial for treating or reducing severity of neurodegeneration in structural targets of brain insulin resistance in AD. ...
Background:
Alzheimer's disease (AD) could be regarded as a brain form of diabetes since insulin resistance and deficiency develop early and progress with severity of neurodegeneration. Preserving insulin's actions in the brain restores function and reduces neurodegeneration. T3D-959 is a dual nuclear receptor agonist currently in a Phase 2a trial in mild-to-moderate AD patients (ClinicalTrials.gov identifier NCT02560753). Herein, we show that T3D-959 improves motor function and reverses neurodegeneration in a sporadic model of AD.
Methods:
Long Evans rats were administered intracerebral (i.c.) streptozotocin (STZ) or normal saline (control) and dosed orally with T3D-959 (1.0 mg/kg/day) or saline for 21 or 28 days. Rotarod tests evaluated motor function. Histopathology with image analysis was used to assess neurodegeneration.
Results:
T3D-959 significantly improved motor performance, and preserved both cortical and normalized white matter structure in i.c STZ-treated rats. T3D-959 treatments were effective when dosed therapeutically, whether initiated 1 day or 7 days after i.c. STZ.
Conclusion:
T3D-959's targeting neuro-metabolic dysfunctions via agonism of PPAR delta and PPAR gamma nuclear receptors provides potential disease modification in AD.
