Group PD Dr. Max Holzer

Development of enrichment protocols and new selective assays for misfolded tau protein​​

Lymphocyte activation test as blood biomarker for Alzheimer's disease​

It is the aim of the project to validate a blood biomarker for the diagnosis of Alzheimer´s disease (AD) as an inexpensive and non-invasive tool which can easily be performed on a large scale at the primary care level and allows to identify patients with high sensitivity at initial stage of AD with mild dementia.

The biomarker is based on AD-associated alterations in the mitogenic response of peripheral lymphocytes. In two previous studies, this biomarker has been assessed in cases with moderate and severe AD. Multivariate scoring demonstrated up to a 90% positive and negative agreement with subject clinical diagnosis. However, here, we will prove this diagnostic tool for its validity in early cases of AD with mild dementia. Herewith, we will contribute to provide measures for detecting patients at very initial stages of the disease which allows for a timely symptomatic treatment and, thus, contributes to a better prognosis.​

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Modelling Alzheimer-like phosphorylation of tau in hibernation​

Alzheimer's disease is a disorder of higher age, characterised by cognitive decline due to a progressive degeneration of neurons beginning in the synaptic compartment. This neurodegenerative process is characterized by the formation of extracellular Aß-plaques and intracellular 'paired helical filaments' made up by a hyperphosphorylated form of the microtubule-associated protein tau.

Recently, we described the reversible formation of hyperphosphorylated tau under physiological conditions of hibernation associated with synaptic regression and cognitive dysfunction. Hibernation, thus, represents a unique model to study under physiological in vivo conditions the molecular regulation and cell biological significance of tau-hyperphosphorylation and its association with regressive synaptic changes in the neuronal fine structure and cognitive function. The present project aims at the analysis of the regulation and pathogenetic role of tau-hyperphosphorylation and its potential links to synaptic regression and cognitive function. This goal will be achieved by a multidisciplinary approach combining enzyme- and protein-biochemical techniques with proteomic, immunohistochemical, ultrastructural and behavioural analyses.

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Interaction of TDP-43 and tau aggregation with the microtubule cytoskeleton in amyothrophic lateral sclerosis

Protein aggregates with phosphorylated Transactivating Response Region (TAR) DNA Binding Protein (pTDP-43) have been identified in motor neurons of ALS patients as pathological hallmark.

The amyotrophic lateral sclerosis (ALS) represents one oft he neurodegenerative diseases and is characterized by a degeneration of motor neurons in the motor cortex and spinal cord. Protein aggregates with phosphorylated Transactivating Response Region (TAR) DNA Binding Protein (pTDP-43) have been identified in motor neurons of ALS patients as pathological hallmark. TDP-43 interacts with the microtubule associated protein 1B (MAP1B), which is responsible for maintenance of microtubule integrity in neuronal axons. This protein is also found in aggregates with TDP-43 enabling an interaction of TDP-43 with the microtubule cytoskeleton. In our project, we aim to investigate the interaction of TDP-43 with the cytoskeleton of motor neurons.​

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