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Publications (47)
Proper staining of cell plasma membrane is indispensable for fluorescence imaging. Herein, we present an array of five anionic cyanine-based turn-on plasma membrane probes with emission spanning from green to near infrared. They are analogous of commonly used MemBright probes family, where two zwitterionic anchor groups are replaced with anionic su...
The interaction of glioblastoma (GB) and microglia is critical due to its implications for tumor progression, immune response modulation, and potential therapeutic strategies. However, the role of microglia in GB pathogenesis remains unclear, especially regarding the in vivo dynamics of their interplay. Performing three-photon imaging in an autocht...
Neuronal activity is accompanied by a net outflow of potassium ions (K⁺) from the intra- to the extracellular space. While extracellular [K⁺] changes during neuronal activity are well characterized, intracellular dynamics have been less well investigated due to lack of respective probes. In the current study we characterized the FRET-based K⁺ biose...
Nanotechnology holds great promise to improve delivery of therapeutics to the brain. Current experimental approaches are, however, hampered by the lack of tools to dynamically monitor cargo delivery in vivo . We developed highly fluorescent lipid nanodroplets (LNDs) that carry a Förster-resonance energy transfer (FRET)-based drug delivery detection...
Incomplete reperfusion of the microvasculature (‘no-reflow’) after ischaemic stroke damages salvageable brain tissue. Previous ex vivo studies suggest pericytes are vulnerable to ischaemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains under-explored in vivo.
Using longitudinal in vivo two-...
Neuronal activity is accompanied by a net outflow of potassium ions (K ⁺ ) from the intra- to the extracellular space. While extracellular [K ⁺ ] changes during neuronal activity are well characterized, intracellular dynamics have been less well investigated due to lack of respective probes. In the current study we characterized the FRET-based K ⁺...
The enormous medical burden of stroke is not only due to the brain injury itself and the acute systemic effects, but is largely determined by chronic comorbidities that develop secondarily after stroke. We hypothesized that the high rate of comorbidity developing after a stroke might have a shared immunological cause, however, the chronic effects o...
Incomplete reperfusion of the microvasculature (no-reflow) after ischemic stroke damages salvageable brain tissue. Previous ex-vivo studies suggest pericytes are vulnerable to ischemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains underexplored in vivo. Using longitudinal in vivo 2-photon...
All clinical BACE1-inhibitor trials for the treatment of Alzheimer's Disease (AD) have failed due to insufficient efficacy or side effects like worsening of cognitive symptoms. However, the scientific evidence to date suggests that BACE1-inhibition could be an effective preventative measure if applied prior to the accumulation of amyloid-beta (Aβ)-...
Misfolded α-synuclein spreads along anatomically connected areas through the brain, prompting progressive neurodegeneration of the nigrostriatal pathway in Parkinson's disease. To investigate the impact of early stage seeding and spreading of misfolded α-synuclein along with the nigrostriatal pathway, we studied the pathophysiologic effect induced...
Given the importance of ion gradients and fluxes in biology, monitoring ions locally at the exterior of the plasma membrane of intact cells in a noninvasive manner is highly desirable but challenging. Classical targeting of genetically encoded biosensors at the exterior of cell surfaces would be a suitable approach; however, it often leads to intra...
CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability,...
Beta-site amyloid-precursor-protein cleaving enzyme 1 (BACE1) is the rate limiting
protease in the production of the amyloid-beta peptide (Ab), which is considered to
be the causative agent in the pathogenesis of Alzheimer’s Disease (AD). Therefore, the
therapeutic potential of pharmacological BACE1 inhibitors is currently tested in clinical
trials...
Video S1. 3D-Reconstruction of the Axonal Network Facilitates Identification of Target Dendrite, Related to Figure 4
Video S3. High-Resolution FIB/SEM 3D-Reconstruction of a Single Tripartite Synapse, Related to Figure 5
Video S2. FIB/SEM 3D-Reconstruction of a Single Dendritic Element, Related to Figure 5
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, w...
BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer’s disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptom...
Alzheimer’s disease is the most prevalent neurodegenerative disorder among elderly persons. Overt accumulation and aggregation of the amyloid β peptide (Aβ) is thought to be the initial causative factor for Alzheimer’s disease. Aβ is produced by sequential proteolytic cleavage of the amyloid precursor protein. Beta-site amyloid precursor protein cl...
Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss...
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...
We demonstrate a 60 mg light video-endomicroscope with a cylindrical shape of the rigid tip of only 1.6 mm diameter and 6.7 mm length. A novel implementation method of the illumination unit in the endomicroscope is presented. It allows for the illumination of the biological sample with fiber-coupled LED light at 455 nm and the imaging of the red-sh...
Background
Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a promising drug target for the treatment of Alzheimer’s disease. Prolonged BACE1 inhibition interferes with structural and functional synaptic plasticity in mice, most likely due to altering the metabolism of BACE1 substrates. Seizure protein 6 (Sez6) is predominantly clea...
Abstract
BACKGROUND:
BACE1 (beta site amyloid precursor protein cleaving enzyme 1) is the rate limiting protease in amyloid β production, hence a promising drug target for the treatment of Alzheimer's disease. Inhibition of BACE1, as the major β-secretase in vivo with multiple substrates, however is likely to have mechanism-based adverse effects....
Alzheimer’s disease (AD) is thought to be caused by accumulation of amyloid-β protein (Aβ), which is a cleavage product of amyloid precursor protein (APP). Transgenic mice overexpressing APP have been used to recapitulate amyloid-β pathology. Among them, APP23 and APPswe/PS1deltaE9 (deltaE9) mice are extensively studied. APP23 mice express APP with...
Background:
BACE1 (beta site amyloid precursor protein cleaving enzyme 1) is the rate limiting protease in amyloid β production, hence a promising drug target for the treatment of Alzheimer's disease. Inhibition of BACE1, as the major β-secretase in vivo with multiple substrates, however is likely to have mechanism-based adverse effects. We explor...
Cognitive decline in Alzheimer's disease is attributed to loss of functional synapses, most likely caused by synaptotoxic, oligomeric forms of amyloid-beta. Many treatment options aim at reducing amyloid-beta levels in the brain, either by decreasing its production or by increasing its clearance. We quantified the effects of immunotherapy directed...
Central nervous glycogen synthase kinase 3β (GSK3β) is implicated in a number of neuropsychiatric diseases, such as bipolar disorder, depression, schizophrenia, fragile X syndrome or anxiety disorder. Many drugs employed to treat these conditions inhibit GSK3β either directly or indirectly. We studied how conditional knockout of GSK3β affected stru...
Although the role of noxious α-synuclein (α-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...
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 beta-amyloid, which is a cleavage product of the amyloid precursor protein. The amyloid-cascade-hypothesis postulates Abeta accumulation as the central event in initiating...
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 α-Synuclein (α-SYN) pathology and olfactory deficit, by examining the integration of adult-born neurons in the olfactory bulb (OB) of A30P α-SYN overexpressing mice. To this end, we c...
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...
FSB-positive cells are vital.
A–A'''' In P301S mice crossed with Thy1-YFPH, 1.9% of FSB-positive cells also contained YFP. No pathological alterations in the dendritic arbors of these cells could be observed. Shown is one co-labelled cell (FSB, AT8, and YFP) next to cells containing either YFP only or FSB and AT8 only. A x–y projection, A'''' x–z p...
