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Project
Inter-relations of protein Tau, GSK3 and Nectin-3 in synaptic structure and plasticity in the hippocampus of mouse models for Alzheimer's disease
Alzheimers Disease (AD) is the most common subtype of dementia, first studied by Alois Alzheimer and published in 1907. He linked clinical observations to the post-mortem pathological analysis, resulting in definition of the main hallmarks of AD: amyloid plaques and neurofibrillary tangles, embedded in an inflamed brain. Amyloid peptides and protein Tau are the two major proteins involved in the pathology. Besides ageing as the major risk-factor for all, are carriers of ApoE4 alleles at extra risk. The complexity of AD finds its origin not only in the complexity of our brain, but also in the multiple genetic, epigenetic and environmental factors that contribute to various extent, and which remain largely to be explored.
The progressive memory decline typically observed in AD patients, most often follows a phase denoted as Mild Cognitive Impairment (MCI). Early dysfunction of synapses, the complex connections between neurons to form circuits, are the accepted cause of the cognitive problems early in the disease. In later stages the central defects become more extensive and debilitating by striking other faculties, which correlates with progressive neuronal cell death and brain atrophy.
Neither objective early diagnosis, nor effective therapy is yet available.
AD pathology is proposed to develop from the brain region known as the entorhinal cortex (ERC) and to spread from there to the hippocampus. Two sets of myelinated axons constitute the perforant (PP) and the temporoammonic (TA) pathways, which functionally link the ERC to the hippocampus. Both regions are essential for learning and memory processes and are most vulnerable in AD.
By analyzing our validated transgenic and viral mouse models for AD and tauopathy, we observed that the TA track was of prime interest. First, we noted in the CA1 stratum lacunosum moleculare (SLM) that expression ofthe synaptic cell-adhesion molecule Nectin-3, was dramatically decreased early in the pathological process. This was accompanied by changes in synapses and in dendritic spines in the CA1 SLM, which is the projectionarea of the TA myelinated axons. Unexpectedly, in Tau transgenic mice severe damage to TA myelinated axons was evident by split and decompactedmyelin sheaths. These can help to explain some of the electrophysiological defects we observed in terms of defective synaptic plasticity and decreased long-term potentiation. Of note, bigenic mice with an additionalactive GSK3β kinase, suffered overall more severe pathology of most aspects.
Excessive phosphorylation of protein Tau is believed to result from an imbalance of kinase and phosphatase activities. GSK3β was identified as Tau-kinase I in AD-brain, while the GSK3α isozymes is far less well studied. We have generated GSK3α-deficient mice to investigate the physiological and pathophysiological functions and roles. We provide evidence that GSK3α is also contributing to learning and memory, and also acts as an effective kinase of mouse and human tau in vivo, next to GSK3β. Moreover, our results prove the non-redundancy of both GSK3 isozymes in brain, and in the systems analyzed.
In conclusion, this PhD thesis provides in vivo evidence for an important role of the axons that connect the ERC to the CA1 via the SLM. The TA axons, and their origin and projection areas, aresubject to specific alterations by expression of human protein Tau. Theanatomical regional defects are analyzed and proposed to underlie specified aspects of the cognitive decline in these mouse models for tauopathy.
The progressive memory decline typically observed in AD patients, most often follows a phase denoted as Mild Cognitive Impairment (MCI). Early dysfunction of synapses, the complex connections between neurons to form circuits, are the accepted cause of the cognitive problems early in the disease. In later stages the central defects become more extensive and debilitating by striking other faculties, which correlates with progressive neuronal cell death and brain atrophy.
Neither objective early diagnosis, nor effective therapy is yet available.
AD pathology is proposed to develop from the brain region known as the entorhinal cortex (ERC) and to spread from there to the hippocampus. Two sets of myelinated axons constitute the perforant (PP) and the temporoammonic (TA) pathways, which functionally link the ERC to the hippocampus. Both regions are essential for learning and memory processes and are most vulnerable in AD.
By analyzing our validated transgenic and viral mouse models for AD and tauopathy, we observed that the TA track was of prime interest. First, we noted in the CA1 stratum lacunosum moleculare (SLM) that expression ofthe synaptic cell-adhesion molecule Nectin-3, was dramatically decreased early in the pathological process. This was accompanied by changes in synapses and in dendritic spines in the CA1 SLM, which is the projectionarea of the TA myelinated axons. Unexpectedly, in Tau transgenic mice severe damage to TA myelinated axons was evident by split and decompactedmyelin sheaths. These can help to explain some of the electrophysiological defects we observed in terms of defective synaptic plasticity and decreased long-term potentiation. Of note, bigenic mice with an additionalactive GSK3β kinase, suffered overall more severe pathology of most aspects.
Excessive phosphorylation of protein Tau is believed to result from an imbalance of kinase and phosphatase activities. GSK3β was identified as Tau-kinase I in AD-brain, while the GSK3α isozymes is far less well studied. We have generated GSK3α-deficient mice to investigate the physiological and pathophysiological functions and roles. We provide evidence that GSK3α is also contributing to learning and memory, and also acts as an effective kinase of mouse and human tau in vivo, next to GSK3β. Moreover, our results prove the non-redundancy of both GSK3 isozymes in brain, and in the systems analyzed.
In conclusion, this PhD thesis provides in vivo evidence for an important role of the axons that connect the ERC to the CA1 via the SLM. The TA axons, and their origin and projection areas, aresubject to specific alterations by expression of human protein Tau. Theanatomical regional defects are analyzed and proposed to underlie specified aspects of the cognitive decline in these mouse models for tauopathy.
Date:1 Feb 2008 → 28 Jun 2013
Keywords:Alheimer's Disease, synapse, peptide mimetic, Cell Adhesion Molecule, memory, GSK3, learning, hippocampus
Disciplines:Genetics, Systems biology, Molecular and cell biology, Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences
Project type:PhD project