Impaired olfactory bulb neurogenesis depends on the presence of human wild-type alpha-synuclein.

Synucleinopathies including Parkinson's disease (PD) are characterized by the accumulation of alpha-synuclein (α-syn) within neural cell bodies and their processes. Transgenic mice overexpressing human wild-type or mutant forms of α-syn under the control of different promoters were developed to analyse the underlying neuropathology of PD. One of the earliest clinical symptoms associated with PD is olfactory impairment. The generation of new neurons persists up to adulthood in mammals, in particular the olfactory bulb (OB). In order to assess this process in relation to α-syn accumulation, we used mice overexpressing human wild-type α-syn under the regulatable control (tet-off) of the calcium/calmodulin-dependent protein kinase IIα-promoter (CaMKII). We observed a decrease in OB neurogenesis in transgenic animals compared to controls using 5-bromo-2'-deoxyuridine (BrdU) to label newly generated cells (neuron-specific nuclear protein; NeuN). After cessation of transgene expression we detected an increase in newly generated cells both in granular (GCL) and glomerular (GLOM) layers of the OB. This led to a rescue of newly generated neurons (BrdU(+)/NeuN(+)) within the GLOM with a distinct specificity for the dopaminergic subpopulation. In contrast, we did not detect a cell-specific rescue of neuronal cells in the GCL suggesting diverse effects of alpha-synucleinopathy in both interneuronal layers of the OB. Colabelling of BrdU with glial markers showed that a differentiation into neither astroglia nor microglia attributed to the observed phenotype in the GCL. In particular, BrdU(+) particles located within microglial cells were predominantly associated close to the membrane therefore the resembling phagocytosed nuclear fragments of BrdU(+) cells. Thus, our study further contributes insights into α-syn accumulation as a causative player in the impairment of adult neurogenesis and emphasizes its diverse role in cell renewal of distinct OB cell layers.

May VE ，Nuber S ，Marxreiter F ，Riess O ，Winner B ，Winkler J ... -  《-》

Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein.

Marxreiter F ，Nuber S ，Kandasamy M ，Klucken J ，Aigner R ，Burgmayer R ，Couillard-Despres S ，Riess O ，Winkler J ，Winner B ... -  《-》

The temporal expression pattern of alpha-synuclein modulates olfactory neurogenesis in transgenic mice.

Schreglmann SR ，Regensburger M ，Rockenstein E ，Masliah E ，Xiang W ，Winkler J ，Winner B ... -  《PLoS One》

Age-related impairment of olfactory bulb neurogenesis in the Ts65Dn mouse model of Down syndrome.

Down syndrome (DS) is a genetic condition caused by triplication of chromosome 21. Widespread neurogenesis reduction during brain development underlies the numerous neurological defects of DS. These defects start to manifest themselves at birth and worsen with age. However, unlike other brain functions, smell is impaired only at advanced life stages, suggesting preservation of olfactory bulb neurogenesis up to adulthood. To clarify this issue, in the current study we examined olfactory bulb (OB) neurogenesis and olfactory function by exploiting the Ts65Dn mouse, a widely used model of DS. We found that in young (15-day-old) Ts65Dn mice, in spite of a reduced proliferation rate in the subventricular zone (SVZ) in comparison with euploid mice, the number of neuroblasts traveling in the rostral migratory stream (RMS), en route to the OB, and the number of new granule neurons added to the OB were similar to those of euploid mice. In mid-age (13-month-old) Ts65Dn mice, however, the proliferation rate in the SVZ was more severely reduced in comparison with euploid mice and the number of neuroblasts in the RMS and new granule neurons added to the OB underwent a reduction. While in young Ts65Dn mice the olfactory function, assessed with the buried food pellet test, was similar to that of euploid mice, in mid-age mice it was significantly impaired. Taken together, results suggest that an age-related reduction in the renewal of OB granule cells may underlie the age-related smell impairment in DS.

Bianchi P ，Bettini S ，Guidi S ，Ciani E ，Trazzi S ，Stagni F ，Ragazzi E ，Franceschini V ，Bartesaghi R ... -  《-》

Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice.

Marxreiter F ，Ettle B ，May VE ，Esmer H ，Patrick C ，Kragh CL ，Klucken J ，Winner B ，Riess O ，Winkler J ，Masliah E ，Nuber S ... -  《-》