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Age-dependent cognitive decline and amygdala pathology in α-synuclein transgenic mice
Neurobiology of Aging, 2007
Intraneuronal ␣-synuclein (␣SYN) inclusions constitute the hallmark lesions of a number of neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. In a transgenic mouse model expressing mutant [A30P]␣SYN under control of the pan-neuronal Thy1 promoter, motor impairment became significant beyond 17 months of age. Cognitive performance was measured in the Morris water maze and upon fear conditioning. At 4 months of age, transgenic mice performed like controls. However, performance in these tasks was significantly impaired in (Thy1)-h[A30P]␣SYN mice at 12 months of age. After completion of the cognition tests, mice were sacrificed and the regional distribution of neuropathology was examined. In contrast to 4 months old animals, 12 months old transgenic mice showed ␣-synucleinopathy in several brain regions, including the central nucleus of the amygdala, which is involved in cognitive behavior of mice, and is susceptible to ␣SYN pathology in human patients. Thus, age-dependent fibrillization of ␣SYN in specific cortical regions concomitant with cognitive decline may reflect dementia with Lewy bodies in a transgenic mouse model. (W. Spooren). exact mode of action is not well understood. Pathologically, ␣SYN can assume a predominantly -sheet conformation and constitutes the major protein component of Lewy bodies (LBs) . The presence of LBs in the brain stem is diagnostic for Parkinson's disease. Moreover, Lewy pathology can spread into the limbic system and the neocortex of Parkinson's disease and LB dementia (DLB) patients .
Tauopathic Changes in the Striatum of A53T α-Synuclein Mutant Mouse Model of Parkinson's Disease
PLoS ONE, 2011
Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the asynuclein (a-Syn) A53T mutant mouse. Elevated levels of a-Syn were observed in striatum of the adult A53T a-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3b, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of a-Syn suggesting that a-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3b and pSer396/404 were also found associated with aggregated a-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, a-Syn remained tightly bound to the cytoskeleton, while p-GSK-3b was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that a-Syn, pSer396/404 Tau and p-GSK-3b co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T a-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies. Citation: Wills J, Credle J, Haggerty T, Lee J-H, Oaks AW, et al. (2011) Tauopathic Changes in the Striatum of A53T a-Synuclein Mutant Mouse Model of Parkinson's Disease. PLoS ONE 6(3): e17953.
Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson’s disease
European Journal of Neuroscience, 2011
Although clinically distinct diseases, tauopathies and synucleinopathies share common genesis and mechanisms, leading to overlapping degenerative changes within neurons. In human postmortem striatum of Parkinson's disease [PD] and PD with dementia, we have recently described elevated levels of tauopathy, indexed as increased hyperphosphorylated Tau [p-Tau].
Tau is essential to -amyloid-induced neurotoxicity
Proceedings of the National Academy of Sciences, 2002
Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar -amyloid peptide (A); neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. In the present study, we analyzed whether tau plays a key role in fibrillar A-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar A. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of A. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of A. These results provide direct evidence supporting a key role for tau in the mechanisms leading to A-induced neurodegeneration in the central nervous system. In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to A-mediated neurodegeneration.
Nature Communications, 2010
The discovery of α-synuclein (αS) mutations has made a major contribution to the understanding of the pathogenesis of α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to β-synuclein (βS) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H βS develop progressive neurodegeneration, as characterized by axonal swelling, astrogliosis and behavioural abnormalities, with memory disorder being more prominent than motor deficits. Furthermore, cross-breeding of P123H βS tg mice with αS tg mice, but not with αS knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H βS is pathogenic and cooperates with pathogenic αS to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H βS in familial DLB. Given the neuritic pathology of βS in sporadic α-synucleinopathies, it appears that alteration of βS can contribute to the pathogenesis of a broad range of α-synucleinopathies.
A β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain
Nature Communications, 2010
The discovery of α-synuclein (αs) mutations has made a major contribution to the understanding of the pathogenesis of α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to β-synuclein (βs) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H βs develop progressive neurodegeneration, as characterized by axonal swelling, astrogliosis and behavioural abnormalities, with memory disorder being more prominent than motor deficits. Furthermore, cross-breeding of P123H βs tg mice with αs tg mice, but not with αs knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H βs is pathogenic and cooperates with pathogenic αs to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H βs in familial DLB. Given the neuritic pathology of βs in sporadic α-synucleinopathies, it appears that alteration of βs can contribute to the pathogenesis of a broad range of α-synucleinopathies.
BMC Neuroscience, 2011
Background: α-synuclein [α-Syn]-mediated activation of GSK-3β leading to increases in hyperphosphorylated Tau has been shown by us to occur in striata of Parkinson's diseased [PD] patients and in animal models of PD. In Alzheimer's disease, tauopathy exists in several brain regions; however, the pattern of distribution of tauopathy in other brain regions of PD or in animal models of PD is not known. The current studies were undertaken to analyze the distribution of tauopathy in different brain regions in a widely used mouse model of PD, the α-Syn overexpressing mouse. Results: High levels of α-Syn levels were seen in the brain stem, with a much smaller increase in the frontal cortex; neither cerebellum nor hippocampus showed any overexpression of α-Syn. Elevated levels of p-Tau, hyperphosphorylated at Ser202, Ser262 and Ser396/404, were seen in brain stem, with lower levels seen in hippocampus. In both frontal cortex and cerebellum, increases were seen only in p-Ser396/404 Tau, but not in p-Ser202 and p-Ser262. p-GSK-3β levels were not elevated in any of the brain regions, although total GSK-3β was elevated in brain stem. p-p38MAPK levels were unchanged in all brain regions examined, while p-ERK levels were elevated in brain stem, hippocampus and cerebellum, but not the frontal cortex. p-JNK levels were increased in brain stem and cerebellum but not in the frontal cortex or hippocampus. Elevated levels of free tubulin, indicating microtubule destabilization, were seen only in the brain stem.
Neuroscience, 2008
Phosphorylation of tau and phosphorylation of ␣-synuclein are crucial abnormalities in Alzheimer's disease (AD) and ␣-synucleinopathies (Parkinson's disease: PD, and dementia with Lewy bodies: DLB), respectively. The presence and distribution of phospho-tau were examined by sub-fractionation, gel electrophoresis and Western blotting in the frontal cortex of cases with AD at different stages of disease progression, PD, DLB pure form and common form, and in age-matched controls. Phospho-tauSer396 has been found in synaptic-enriched fractions in AD frontal cortex at entorhinal/transentorhinal, limbic and neocortical stages, thus indicating early tau phosphorylation at the synapses in AD before the occurrence of neurofibrillary tangles in the frontal cortex. Phospho-tauSer396 is also found in synaptic-enriched fractions in the frontal cortex in PD and DLB pure and common forms, thus indicating increased tau phosphorylation at the synapses in these ␣-synucleinopathies. Densitometric studies show between 20% and 40% phospho-tauSer396, in relation with tau-13, in synaptic-enriched fractions of the frontal cortex in AD stages I-III, and in PD and DLB. The percentage reaches about 95% in AD stage V and DLB common form. Yet tau phosphorylation characteristic of neurofibrillary tangles, as revealed with the AT8 antibody, is found in the synaptic fractions of the frontal cortex only at advanced stages of AD. Increased phosphorylated ␣-synucle-inSer129 levels are observed in the synaptic-enriched fractions of the frontal cortex in PD and DLB pure and common forms, and in advanced stages of AD. Since tau-hyperphosphorylation has implications in microtubule assembly, and phosphorylation of ␣-synuclein at Ser129 favors ␣-synuclein aggregation, it can be suggested that synapses are targets of abnormal tau and ␣-synuclein phosphorylation in both groups of diseases. Tau phosphorylation at Ser396 has also been found in synapticenriched fractions in 12-month-old transgenic mice bearing the A53T ␣-synuclein mutation.
Loss of Tau Expression Attenuates Neurodegeneration Associated with α-Synucleinopathy
Research Square (Research Square), 2021
Background: Neuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson's Disease and related Dementia with Lewy Bodies. Studies indicate to bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive de cits that require microtubule-associated protein tau expression. However, the role of tau in development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. Methods: Transgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau-/mice to generate TgA53T/mTau-/-. To achieve uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed brils (PFF) to non-transgenic (nTg), TgA53T, TgA53T/mTau-/-, and mTau-/mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Results: Loss of tau expression signi cantly delayed onset of motor de cits in the TgA53T model and delayed α-synucleinopathy disease progression, as evidenced by a signi cant reduction in