Loss of Medial Septum Cholinergic Neurons in THY-Tau22 Mouse Model: What Links with tau Pathology?

Université Lille Nord de France, Lille, France.
Current Alzheimer research (Impact Factor: 3.89). 05/2011; 8(6):633-8. DOI: 10.2174/156720511796717230
Source: PubMed


Alzheimer's disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, the mechanisms underlying cholinergic neurons degeneration remain uncertain. The present study aimed to investigate the relationship between neurofibrillary degeneration and cholinergic defects in AD using THY-Tau22 transgenic mouse model exhibiting a major hippocampal AD-like tau pathology and hyperphosphorylated tau species in the septohippocampal pathway. Here, we report that at a time THY-Tau22 mice display strong reference memory alterations, the retrograde transport of fluorogold through the septohippocampal pathway is altered. This impairment is associated with a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum. Analysis of nerve growth factor (NGF) levels supports an accumulation of the mature neurotrophin in the hippocampus of THY-Tau22 mice, consistent with a decrease of its uptake or retrograde transport by cholinergic terminals. Finally, our data strongly support that tau pathology could be instrumental in the cholinergic neuronal loss observed in AD.

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Available from: David Blum, Oct 05, 2015
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    • "Interestingly, at that time point, THY-Tau22 mice exhibit septo-hippocampal tau pathology accompanied by altered retrograde transport from hippocampus to medial septum (Belarbi K et al., 2009) with an accumulation of the nerve growth factor (NGF) levels in the hippocampus consistent with a decrease of its uptake or retrograde transport by cholinergic terminals (Belarbi K et al., in press). Recent data indicate that voluntary exercise prevented memory alterations in these transgenic mice and increased mRNA levels of genes involved in cholesterol trafficking such as NPC1 and NPC2 (Belarbi K et al., 2011). "
    Proteomics - Human Diseases and Protein Functions, Edited by Tsz Kwong Man, 02/2012: chapter The Microtubule-Dissociating Tau in Neurological Disorders: pages 291-326; InTech., ISBN: 978-953-307-832-8
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    ABSTRACT: Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.
    Biochemical Society Transactions 08/2010; 38(4):967-72. DOI:10.1042/BST0380967 · 3.19 Impact Factor
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