A30P alpha-Synuclein interferes with the stable integration of adult-born neurons into the olfactory network

Impaired olfaction is an early symptom in Parkinson disease (PD),although the exact cause is as yet unknown. Here, we investigated the link between PD-related mutant alpha-Synuclein (alpha-SYN) pathology and olfactory deficit, by examining the integration of adult-born neurons in the olfactory bulb (OB) of A30P alpha-SYN overexpressing mice. To this end, we chose to label one well-known vulnerable subpopulation of adult-born cells, the dopaminergic neurons. Using in vivo two-photon imaging, we followed the dynamic process of neuronal turnover in transgenic A30P alpha-SYN and wild-type mice over a period of 2.5 months. Our results reveal no difference in the number of cells that reach, and possibly integrate into, the glomerular layer in the OB. However, in mutant transgenic mice these new neurons have a significantly shortened survival, resulting in an overall reduction in the addition of neurons to the glomerular layer over time. We therefore propose unstable integration and impaired homeostasis of functional new neurons as a likely contributor to odour discrimination deficits in mutant alpha-SYN mice

A30P alpha-Synuclein interferes with the stable integration of adult-born neurons into the olfactory network

Impaired olfaction is an early symptom in Parkinson disease (PD),although the exact cause is as yet unknown. Here, we investigated the link between PD-related mutant alpha-Synuclein (alpha-SYN) pathology and olfactory deficit, by examining the integration of adult-born neurons in the olfactory bulb (OB) of A30P alpha-SYN overexpressing mice. To this end, we chose to label one well-known vulnerable subpopulation of adult-born cells, the dopaminergic neurons. Using in vivo two-photon imaging, we followed the dynamic process of neuronal turnover in transgenic A30P alpha-SYN and wild-type mice over a period of 2.5 months. Our results reveal no difference in the number of cells that reach, and possibly integrate into, the glomerular layer in the OB. However, in mutant transgenic mice these new neurons have a significantly shortened survival, resulting in an overall reduction in the addition of neurons to the glomerular layer over time. We therefore propose unstable integration and impaired homeostasis of functional new neurons as a likely contributor to odour discrimination deficits in mutant alpha-SYN mice

In vivo imaging reveals sigmoidal growth kinetic of β-amyloid plaques

A major neuropathological hallmark of Alzheimer's disease is the deposition of amyloid plaques in the brains of affected individuals. Amyloid plaques mainly consist of fibrillar β-amyloid, which is a cleavage product of the amyloid precursor protein. The amyloid-cascade-hypothesis postulates Aβ accumulation as the central event in initiating a toxic cascade leading to Alzheimer's disease pathology and, ultimately, loss of cognitive function. We studied the kinetics of β-amyloid deposition in Tg2576 mice, which overexpress human amyloid precursor protein with the Swedish mutation. Utilizing long-term two-photon imaging we were able to observe the entire kinetics of plaque growth in vivo. Essentially, we observed that plaque growth follows a sigmoid-shaped curve comprising a cubic growth phase, followed by saturation. In contrast, plaque density kinetics exhibited an asymptotic progression. Taking into account the fact that a critical concentration of Aβ is required to seed new plaques, we can propose the following kinetic model of β-amyloid deposition in vivo. In the early cubic phase, plaque growth is not limited by Aβ concentration and plaque density increases very fast. During the transition phase, plaque density stabilizes whereas plaque volume increases strongly reflecting a robust growth of the plaques. In the late asymptotic phase, Aβ peptide production becomes rate-limiting for plaque growth. In conclusion, the present study offers a direct link between in vitro and in vivo studies facilitating the translation of Aβ-lowering strategies from laboratory models to patients

Pathological alpha-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb

Although the role of noxious alpha-synuclein (alpha-SYN) in the degeneration of midbrain dopaminergic neurons and associated motor deficits of Parkinson's disease is recognized, its impact on non-motor brain circuits and related symptoms remains elusive. Through combining in vivo two-photon imaging with time-coded labelling of neurons in the olfactory bulb of A30P alpha-SYN transgenic mice, we show impaired growth and branching of dendrites of adult-born granule cells (GCs),with reduced gain and plasticity of dendritic spines. The spine impairments are especially pronounced during the critical phase of integration of new neurons into existing circuits. Functionally, retarded dendritic expansion translates into reduced electrical capacitance with enhanced intrinsic excitability and responsiveness of GCs to depolarizing inputs, while the spine loss correlates with decreased frequency of AMPA-mediated miniature EPSCs. Changes described here are expected to interfere with the functional integration and survival of new GCs into bulbar networks, contributing towards olfactory deficits and related behavioural impairments

Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice.

Tauopathies are widespread neurodegenerative disorders characterised by the intracellular accumulation of hyperphosphorylated tau. Especially in Alzheimer's disease, pathological alterations in the retina are discussed as potential biomarkers to improve early diagnosis of the disease. Using mice expressing human mutant P301S tau, we demonstrate for the first time a straightforward optical approach for the in vivo detection of fibrillar tau in the retina. Longitudinal examinations of individual animals revealed the fate of single cells containing fibrillar tau and the progression of tau pathology over several months. This technique is most suitable to monitor therapeutic interventions aimed at reducing the accumulation of fibrillar tau. In order to evaluate if this approach can be translated to human diagnosis, we tried to detect fibrillar protein aggregates in the post-mortem retinas of patients that had suffered from Alzheimer's disease or Progressive Supranuclear Palsy. Even though we could detect hyperphosphorylated tau, we did not observe any fibrillar tau or Aß aggregates. In contradiction to previous studies, our observations do not support the notion that Aβ or tau in the retina are of diagnostic value in Alzheimer's disease

Neurogenesis from Sox2 expressing cells in the adult cerebellar cortex

We identified a rare undifferentiated cell population that is intermingled with the Bergmann glia of the adult murine cerebellar cortex, expresses the stem cell markers Sox2 and Nestin, and lacks markers of glial or neuronal differentiation. Interestingly, such Sox2(+) S100(-) cells of the adult cerebellum expanded after adequate physiological stimuli in mice (exercise), and Sox2(+) precursors acquired positivity for the neuronal marker NeuN over time and integrated into cellular networks. In human patients, SOX2(+) S100(-) cells similarly increased in number after relevant pathological insults (infarcts), suggesting a similar expansion of cells that lack terminal glial differentiation

Label-free 3D-CLEM Using Endogenous Tissue Landmarks

Emerging 3D correlative light and electron microscopy approaches enable studying neuronal structure-function relations at unprecedented depth and precision. However, established protocols for the correlation of light and electron micrographs rely on the introduction of artificial fiducial markers, such as polymer beads or near-infrared brandings, which might obscure or even damage the structure under investigation. Here, we report a general applicable "flat embedding" preparation, enabling high-precision overlay of light and scanning electron micrographs, using exclusively endogenous landmarks in the brain: blood vessels, nuclei, and myelinated axons. Furthermore, we demonstrate feasibility of the workflow by combining in vivo 2-photon microscopy and focused ion beam scanning electron microscopy to dissect the role of astrocytic coverage in the persistence of dendritic spines

Radiation enhancement and "temperature" in the collapse regime of gravitational scattering

We generalize the semiclassical treatment of graviton radiation to gravitational scattering at very large energies $\sqrt{s}\gg m_P$ and finite scattering angles $\Theta_s$, so as to approach the collapse regime of impact parameters $b \simeq b_c \sim R\equiv 2G\sqrt{s}$. Our basic tool is the extension of the recently proposed, unified form of radiation to the ACV reduced-action model and to its resummed-eikonal exchange. By superimposing that radiation all-over eikonal scattering, we are able to derive the corresponding (unitary) coherent-state operator. The resulting graviton spectrum, tuned on the gravitational radius $R$, fully agrees with previous calculations for small angles $\Theta_s\ll 1$ but, for sizeable angles $\Theta_s(b)\leq \Theta_c = O(1)$ acquires an exponential cutoff of the large $\omega R$ region, due to energy conservation, so as to emit a finite fraction of the total energy. In the approach-to-collapse regime of $b\to b_c^+$ we find a radiation enhancement due to large tidal forces, so that the whole energy is radiated off, with a large multiplicity $\langle N \rangle\sim Gs \gg 1$ and a well-defined frequency cutoff of order $R^{-1}$. The latter corresponds to the Hawking temperature for a black hole of mass notably smaller than $\sqrt{s}$.Comment: 5 pages, 2 figures, talk presented at the European Physical Society Conference on High Energy Physics, 5-12 July, Venice, Ital

Pathological alpha-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb

Although the role of noxious alpha-synuclein (alpha-SYN) in the degeneration of midbrain dopaminergic neurons and associated motor deficits of Parkinson's disease is recognized, its impact on non-motor brain circuits and related symptoms remains elusive. Through combining in vivo two-photon imaging with time-coded labelling of neurons in the olfactory bulb of A30P alpha-SYN transgenic mice, we show impaired growth and branching of dendrites of adult-born granule cells (GCs),with reduced gain and plasticity of dendritic spines. The spine impairments are especially pronounced during the critical phase of integration of new neurons into existing circuits. Functionally, retarded dendritic expansion translates into reduced electrical capacitance with enhanced intrinsic excitability and responsiveness of GCs to depolarizing inputs, while the spine loss correlates with decreased frequency of AMPA-mediated miniature EPSCs. Changes described here are expected to interfere with the functional integration and survival of new GCs into bulbar networks, contributing towards olfactory deficits and related behavioural impairments