Anna Mietelska-Porowska

Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction

Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and its interaction with several proteins play an important regulatory role in the physiology of tau. As a consequence of abnormal modifications and expression, tau is redistributed from neuronal processes to the soma and forms toxic oligomers or aggregated deposits. The accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementia disorders known as tauopathies. Dysfunction of tau protein may contribute to collapse of cytoskeleton, thereby causing improper anterograde and retrograde movement of motor proteins and their cargos on microtubules. These disturbances in intraneuronal signaling may compromise synaptic transmission as well as trophic support mechanisms in neurons.

The cholinergic system, nerve growth factor and the cytoskeleton.

Cholinergic neurons of the basal forebrain provide the major cholinergic innervation to the cortex and hippocampus, and play a key role in memory and attentional processes. Dysfunction of basal forebrain cholinergic neurons (BFCN) is a cardinal feature of Alzheimers disease (AD) and correlates with cognitive decline. Survival of BFCN neurons depends upon binding of nerve growth factor (NGF), which is synthesized and secreted by cells in the cortex and hippocampus, with high-affinity (TrkA) and low-affinity (p75(NTR)) neurotrophin receptors produced within BFCN neurons. NGF released from target cells activates TrkA on axon terminals and triggers activation of PI3K/Akt, MEK/ERK, and PLCγ (phospholipase C) signaling pathways. The signal then travels retrogradely along axon to cell body to promote neuronal survival. However, the nature of the retrograde signal remains mysterious. p75(NTR) receptors could mediate a fundamentally different signaling pathway leading to apoptic cell death. Dysfunction of NGF and its receptors has been suggested to underlie the selective degeneration of the BFCN in end stage Alzheimer disease. In this regard, NGF, the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of AD. This review focuses on NGF-cholinergic dependency, NGF/receptor binding, signal transduction, retrograde transport, regulation of specific cellular endpoints, and the potential involvement of cytoskeleton dysfunction in defected NGF signaling.

T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers

Alzheimers disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers.

Calcyclin binding protein and Siah-1 interacting protein in Alzheimer's disease pathology: neuronal localization and possible function.

The calcyclin binding protein and Siah-1 interacting protein (CacyBP/SIP) protein was shown to play a role in the organization of microtubules. In this work we have examined the neuronal distribution and possible function of CacyBP/SIP in cytoskeletal pathophysiology. We have used brain tissue from Alzheimers disease (AD) patients and from transgenic mice modeling 2 different pathologies characteristic for AD: amyloid and tau. In the brain from AD patients, CacyBP/SIP was found to be almost exclusively present in neuronal somata, and in control patients it was seen in the somata and neuronal processes. In mice doubly transgenic for amyloid precursor protein and presenilin 1 there was no difference in CacyBP/SIP neuronal localization in comparison with the nontransgenic animals. By contrast in tau transgenic mice, localization of CacyBP/SIP was similar to that observed for AD patients. To find the relation between CacyBP/SIP and tau we examined dephosphorylation of tau by CacyBP/SIP. We found that indeed it exhibited phosphatase activity toward tau. Altogether, our results suggest that CacyBP/SIP might play a role in AD pathology.

Search for Alzheimer's disease biomarkers in blood cells: hypotheses-driven approach

Current Alzheimers disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients.

TREATMENT WITH LITHIUM CHLORIDE ALLEVIATES MORPHOLOGICAL AND COGNITIVE IMPAIRMENT PROVOKED BY EXCESSIVE TAU IN PHARMACOLOGICALLY INDUCED RAT MODEL OF HUMAN TAUOPATHY

WEDNESDAY, JULY 16, 2014 POSTER PRESENTATIONS P4 P4-001 CHANGES IN FRONTOCORTICAL INTERSTITIAL FLUID LEVELS OF BETA-AMYLOID AND TAU PROTEIN IN TRANSGENIC MICE MODELS OF ALZHEIMER’S DISEASE Alain Gobert, Gaelle Rollin-Jego, Fabrice Iop, Jean Michel Rivet, Dominique Favale, Laurence Danober, Sophie Dix, Christian Czech, Ozmen Laurence, Jill Richardson, Esther Schenker, Institut de Recherches Servier, Croissy sur Seine, France; Institut de Recherches Servier, Croissy sur Seine, France; Institut de Recherches Servier, Croissy sur Seine, France; Eli Lilly, Lilly Research Centre, Surrey, United Kingdom; CNS Research, Hoffmann-La Roche AG, Basel, Switzerland; F. Hoffmann-LaRoche AG, Basel, Switzerland; GlaxoSmithKline Research and Development, China Group, Stevenage, United Kingdom; Institut de Recherches Servier, Croissy sur Seine, France. Contact e-mail: alain.gobert@fr.netgrs.com