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. A promising model is the Line 61 α-synuclein transgenic mouse that expresses the transgene under control of the Thy-1 promoter. RESULTS: Here, we show an extended characterization of this mouse model over age. To this end, we analyzed animals for the progression of human and mouse protein expression levels in different brain areas as well as motor and memory deficits. Our results show, that Line 61 mice exhibited an age dependent increase of α-synuclein protein levels in the hippocampus but not the striatum. While murine α-synuclein was also increased with age, it was lower expressed in Line 61 mice than in non-transgenic littermates. At the age of 9 months animals exhibited increased neuroinflammation. Furthermore, we found that Line 61 mice showed severe motor deficits as early as 1 month of age as assessed by the wire hanging and nest building tests. At later ages, initial motor deficits were validated with the RotaRod, pasta gnawing and beam walk tests. At 8 months of age animals exhibited emotional memory deficits as validated with the contextual fear conditioning test. CONCLUSION: In summary, our results strengthen and further expand our knowledge about the Line 61 mouse model, emphasizing this mouse model as a valuable in vivo tool to test new compounds directed against synucleinopathies.

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. Only soluble total tau and phosphorylated tau (ptau at residue Thr(181), Ser(199), Thr(231) and Thr(235)), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser(396) and Ser(404) in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.

Quantitative evaluation of orofacial motor function in mice: The pasta gnawing test, a voluntary and stress-free behavior test.

BACKGROUND: Evaluation of motor deficits in rodents is mostly restricted to limb motor tests that are often high stressors for the animals. NEW METHOD: To test rodents for orofacial motor impairments in a stress-free environment, we established the pasta gnawing test by measuring the biting noise of mice that eat a piece of spaghetti. Two parameters were evaluated, the biting speed and the biting peaks per biting episode. To evaluate the power of this test compared to commonly used limb motor and muscle strength tests, three mouse models of Parkinson's disease, amyotrophic lateral sclerosis and Niemann-Pick disease were tested in the pasta gnawing test, RotaRod and wire suspension test. RESULTS: Our results show that the pasta gnawing test reliably displays orofacial motor deficits. COMPARISON WITH EXISTING METHODS: The test is especially useful as additional motor test in early onset disease models, since it shows first deficits later than the RotaRod or wire suspension test. The test depends on a voluntary eating behavior of the animal with only a short-time food deprivation and should thus be stress-free. CONCLUSIONS: The pasta gnawing test represents a valuable tool to analyze orofacial motor deficits in different early onset disease models.

[Results of pathologico-anatomic findings on the synthetic architecture of the human brain]. / Ergebnisse pathologisch-anatomischer Befunde zur synthetischen Architektur des menschlichen Gehirns.

The synthetic architecture of the brain reflects the dynamics of life, which require harmony. In man, the goal of the energy recognizable in this architecture differs from that in animals. Individual reactions are the results of the different spatial architecture. Special enzyme properties have been pointed out. These are responsible for differences in structure and relationships. Such differences are necessary for the various biologic demands. They also explain many clinical findings.

[Causes and effects of synthesis differences of the dorsomedial nucleus of the thalamus]. / Ursachen und Folgen der Syntheseunterschiede vom Nucleus mediodorsalis des Thalamus.

Attention has been paid to the connection between morphogenesis and the synthesis of tissue structures with regard to their effects upon the functions and, on the other hand, their dependence on diseases and changes in blood circulation. A synthetic interpretation of the brain leads to the picture of a total ("ganzheitlich") order which, by itself, helps to explain the existence of a harmony. We have pointed to limitations in drawing parallels (in a biological sense) between human beings and animals. Above all, this becomes clear in the case of the Ncl. medio-dorsalis of the thalamus: Here is a functional system, the importance of which (for psycho-pathological conditions and disturbances) can be observed. Thereby, lacks of functions that are due to the dynamics of vital processes, can be explained. "Functional morphae" (Gestalten) are only those that are of a certain use. The variability of the building elements of the Ncl. medio-dorsalis is greater than its functions would require. However, there may be border-line cases, being explicable as a result of micro-evolution. The "change of forms" ("Formwandel") can finally help to illustrate certain pathological formations whose detailed interpretation is not entirely possible.

[Structure and evaluation of the paramedian side of thalamus]. / Bau und Beurteilung der paramedianen Seite des Thalamus.

The adhaesio interthalamica in humans as apposed to animals is formed only by the nucleus reuniens which is of very variable size and which is conspicuously small if there is no adhaesio interthalamica. It is larger than in animals and is probably of special importance for humans. Its fliber connections have not been elucidadat and its effects on other parts of the brain cannot be determined with certainty. As the adhaesio interthalamica may be enlarged under certain condition-and is frequently preserved in sensecence, so it is probably of special significance for humans. Similar findings have been obtained for the adacent paramedian part of the thalamus the cells of which are irregularly distributed.

[Synthetic method of evaluating evolutionary manifestations]. / Synthetische Beurteilung von Erscheinungsformen der Evolution.

Evolution means life as a dynamic process. It consists of many subprocesses which belong to each other by way of synthesis (meaning that they cannot be conceived of in a purely analytical manner). To grant further existence, these subprocesses must lead to a harmony. Morphological, chemical, and physiological processes are joining each other. This results in certain formations and variations. Furthermore, one must take into account physical and psychic factors. There are organic contexts but the functions of which cannot explain merely by analyzing their single parts. Sudden changes occur that are mirrored in our knowledge. Evolution is not identical with development (for this, the process of growing and the naturation of enzymes must be taken into account). However, evolution and development have in common that they can only be understood in a dynamic, not in a static way.