Motor deficits and brain pathology in the Parkinson's disease mouse model hA53Ttg.

Background: Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of α-synuclein (α-syn) aggregates. The A53T missense point mutation occurs in autosomal dominant familial PD and has been found to promote the aggregation of α-syn. To investigate the role of the A53T mutation in PD, researchers have developed various mouse models with this mutation.

Effect of astaxanthin in type-2 diabetes -induced APPxhQC transgenic and NTG mice.

Objectives: Aggregation and misfolding of amyloid beta (Aβ) and tau proteins, suggested to arise from post-translational modification processes, are thought to be the main cause of Alzheimer's disease (AD). Additionally, a plethora of evidence exists that links metabolic dysfunctions such as obesity, type 2 diabetes (T2D), and dyslipidemia to the pathogenesis of AD. We thus investigated the combinatory effect of T2D and human glutaminyl cyclase activity (pyroglutamylation), on the pathology of AD and whether astaxanthin (ASX) treatment ameliorates accompanying pathophysiological manifestations.

Gadolinium Presence in Rat Skin: Assessment of Histopathologic Changes Associated with Small Fiber Neuropathy.

Background The presence of gadolinium traces in the skin after administration of gadolinium-based contrast agents (GBCAs) raised safety concerns regarding a potential association with small fiber neuropathy (SFN). Purpose To investigate signs of SFN in rat foot pads by quantification of the intraepidermal nerve fiber density (IENFD) after multiple GBCA administrations and to evaluate gadolinium concentration, chemical species, and clearance. Materials and Methods Fifty rats received eight intravenous injections of either gadodiamide, gadobutrol, gadoterate, gadoteridol (8 × 0.

Characterization of an APP/tau rat model of Alzheimer's disease by positron emission tomography and immunofluorescent labeling.

Background: To better understand the etiology and pathomechanisms of Alzheimer's disease, several transgenic animal models that overexpress human tau or human amyloid-beta (Aβ) have been developed. In the present study, we generated a novel transgenic rat model by cross-breeding amyloid precursor protein (APP) rats with tau rats. We characterized this model by performing positron emission tomography scans combined with immunofluorescent labeling and cerebrospinal fluid analyses.

Evaluation of Neuropathological Features in the SOD1-G93A Low Copy Number Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) still depicts an incurable and devastating disease. Drug development efforts are mostly based on superoxide dismutase 1 gene (SOD1)-G93A mice that present a very strong and early phenotype, allowing only a short time window for intervention. An alternative mouse model is available, that is based on the same founder line but has a reduced SOD1-G93A copy number, resulting in a weaker and delayed phenotype.

Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer's Disease.

Background: Preclinical Alzheimer's disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research.

Quantification of Huntington's Disease Related Markers in the R6/2 Mouse Model.

Huntington's disease (HD) is caused by an expansion of CAG triplets in the huntingtin gene, leading to severe neuropathological changes that result in a devasting and lethal phenotype. Neurodegeneration in HD begins in the striatum and spreads to other brain regions such as cortex and hippocampus, causing motor and cognitive dysfunctions. To understand the signaling pathways involved in HD, animal models that mimic the human pathology are used.

Constant Levels of Tau Phosphorylation in the Brain of htau Mice.

Excessive tau phosphorylation is the hallmark of tauopathies. Today's research thus focusses on the development of drugs targeting this pathological feature. To test new drugs in preclinical studies, animal models are needed that properly mimic this pathological hallmark.

Correlation of pyroglutamate amyloid β and ptau Ser202/Thr205 levels in Alzheimer's disease and related murine models.

Senile plaques frequently contain Aβ-pE(3), a N-terminally truncated Aβ species that is more closely linked to AD compared to other Aβ species. Tau protein is highly phosphorylated at several residues in AD, and specifically phosphorylation at Ser202/Thr205 is known to be increased in AD. Several studies suggest that formation of plaques and tau phosphorylation might be linked to each other.

Transgene integration causes RARB downregulation in homozygous Tg4-42 mice.

Alzheimer's disease can be modelled by different transgenic mouse strains. To gain deeper insight into disease model mechanisms, the previously described Tg4-42 mouse was analysed for transgene integration. On RNA/DNA level the transgene integration resulted in more than 20 copy numbers and further caused a deletion of exon 2 of the retinoic acid receptor beta.

Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease.

Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum.

Hepatic and neuronal phenotype of NPC1 mice.

Niemann-Pick type C disease (NPC) is a fatal autosomal recessive disorder characterized by a defect in the intracellular transport of lipoproteins leading to the accumulation of lipids in diverse tissues. A visceral and neuronal phenotype mimicking human NPC1 disease has been described in NPC1 mutant mice. These mice are by now the most widely used NPC1 rodent model to study NPC and developmental compounds against this devastating disease.

Phosphorylation of different tau sites during progression of Alzheimer's disease.

Alzheimer's disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles.

mTh1 driven expression of hTDP-43 results in typical ALS/FTLD neuropathological symptoms.

Transgenic mouse models are indispensable tools to mimic human diseases and analyze the effectiveness of related new drugs. For a long time amyotrophic lateral sclerosis (ALS) research depended on only a few mouse models that exhibit a very strong and early phenotype, e.g.

Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable for therapy development.

SEN1500, a novel oral amyloid-β aggregation inhibitor, attenuates brain pathology in a mouse model of Alzheimer's disease.

Introduction: Amyloid-β (Aβ) aggregation is thought to be a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The development of new drugs inhibiting the Aβ aggregation process is, therefore, important. SEN1500, an orally bioavailable and CNS-penetrant Aβ aggregation inhibitor, has previously been shown to reduce spatial learning and memory deficits in an APP transgenic mouse model.

Early start of progressive motor deficits in Line 61 α-synuclein transgenic mice.

Background: Synucleinopathies such as Parkinson's disease or multiple system atrophy are characterized by Lewy bodies in distinct brain areas. These aggregates are mainly formed by α-synuclein inclusions, a protein crucial for synaptic functions in the healthy brain. Transgenic animal models of synucleinopathies are frequently based on over-expression of human wild type or mutated α-synuclein under the regulatory control of different promoters.

Early and progressive microstructural brain changes in mice overexpressing human α-Synuclein detected by diffusion kurtosis imaging.

Diffusion kurtosis imaging (DKI) is sensitive in detecting α-Synuclein (α-Syn) accumulation-associated microstructural changes at late stages of the pathology in α-Syn overexpressing TNWT-61 mice. The aim of this study was to perform DKI in young TNWT-61 mice when α-Syn starts to accumulate and to compare the imaging results with an analysis of motor and memory impairment and α-Syn levels. Three-month-old (3mo) and six-month-old (6mo) mice underwent DKI scanning using the Bruker Avance 9.

Time course and progression of wild type α-synuclein accumulation in a transgenic mouse model.

Background: Progressive accumulation of α-synuclein (α-Syn) protein in different brain regions is a hallmark of synucleinopathic diseases, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. α-Syn transgenic mouse models have been developed to investigate the effects of α-Syn accumulation on behavioral deficits and neuropathology. However, the onset and progression of pathology in α-Syn transgenic mice have not been fully characterized.

Elevated levels of soluble total and hyperphosphorylated tau result in early behavioral deficits and distinct changes in brain pathology in a new tau transgenic mouse model.

Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay.

Expression of the neuregulin receptor ErbB4 in the brain of the rhesus monkey (Macaca mulatta).

We demonstrated recently that frontal cortical expression of the Neuregulin (NRG) receptor ErbB4 is restricted to interneurons in rodents, macaques, and humans. However, little is known about protein expression patterns in other areas of the brain. In situ hybridization studies have shown high ErbB4 mRNA levels in various subcortical areas, suggesting that ErbB4 is also expressed in cell types other than cortical interneurons.

Conserved interneuron-specific ErbB4 expression in frontal cortex of rodents, monkeys, and humans: implications for schizophrenia.

Background: Neuregulin-1 and ErbB4 are genetically associated with schizophrenia, and detailed knowledge of the cellular and subcellular localization of ErbB4 is important for understanding how neuregulin-1 regulates neuronal network activity and behavior. Expression of ErbB4 is restricted to interneurons in the rodent hippocampus and cortex. However, controversy remains about the cellular expression pattern in primate brain and its subcellular distribution in postsynaptic somatodendritic locations versus presynaptic terminals.

Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus.

NRG1 and ERBB4 have emerged as some of the most reproducible schizophrenia risk genes. Moreover, the Neuregulin (NRG)/ErbB4 signaling pathway has been implicated in dendritic spine morphogenesis, glutamatergic synaptic plasticity, and neural network control. However, despite much attention this pathway and its effects on pyramidal cells have received recently, the presence of ErbB4 in these cells is still controversial.

Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice.

Neuregulins (NRGs) are ligands of ErbB receptor tyrosine kinases. The NRG1-ErbB4 pathway has been shown to modulate hippocampal synaptic plasticity and network oscillations in the adult rodent brain. To identify cells that mediate these effects, here we determine the expression pattern of ErbB4 in four functionally distinct classes of interneurons that represent the majority of all inhibitory neurons in the adult hippocampus.