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Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease.

Crespo-Biel N, Theunis C, Van Leuven F - Int J Alzheimers Dis (2012)

Bottom Line: Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions.The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments.Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Experimental Genetics Group (LEGTEGG), Department of Human Genetics, KU Leuven, Campus Gasthuisberg ON1-06.602, Herestraat 49, 3000 Leuven, Belgium.

ABSTRACT
The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis of a wide variety of brain-damaging disorders, known as tauopathies. These include Alzheimer's disease (AD), denoted as secondary tauopathy because of the obligatory combination with amyloid pathology. In all tauopathies, protein Tau becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate as threads in neuropil and as tangles in soma. The argyrophilic neurofibrillary threads and tangles, together denoted as NFT, provide the postmortem pathological diagnosis for all tauopathies. In AD, neurofibrillary threads and tangles (NFTs) are codiagnostic with amyloid depositions but their separated and combined contributions to clinical symptoms remain elusive. Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions. Conversely, the biochemical and pathological timeline is not exactly known in human tauopathy, but experimental models point to smaller Tau-aggregates, termed oligomers or multimers, as synaptotoxic in early stages. The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments. Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.

No MeSH data available.


Related in: MedlinePlus

Selected biochemical and pathological characteristics of transgenic mouse models. (a) Soluble and sarkosyl insoluble fractions of Tau (SInT) were isolated as described [10] and proteins separated by SDS-PAGE on 10% tris-glycine gels. After transfer to nitrocellulose membranes, proteins were immunoblotted with either anti-pS396 (Invitrogen, Carlsbad, CA) or HT7 (Innogenetics, Gent, Belgium). Phosphorylated human Tau (apparent Mr about 64 kDa) is evident in soluble fractions from forebrain and brainstem of all three genotypes. SInT is evident in forebrain and brainstem of terminal TPLH and old biAT mice (age 15 months) but not in the brainstem of old biGT mice (15 months). (b) Immunohistochemistry with AT100 on free-floating sagittal sections of terminal mice shows tangles and neuropil threads in cortex and brainstem of all genotypes, but significantly less in the brainstem of biGT mice. Tauopathy is minimal or absent in pyramidal neurons of the hippocampus of terminal Tau.P301L transgenic mice.
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fig1: Selected biochemical and pathological characteristics of transgenic mouse models. (a) Soluble and sarkosyl insoluble fractions of Tau (SInT) were isolated as described [10] and proteins separated by SDS-PAGE on 10% tris-glycine gels. After transfer to nitrocellulose membranes, proteins were immunoblotted with either anti-pS396 (Invitrogen, Carlsbad, CA) or HT7 (Innogenetics, Gent, Belgium). Phosphorylated human Tau (apparent Mr about 64 kDa) is evident in soluble fractions from forebrain and brainstem of all three genotypes. SInT is evident in forebrain and brainstem of terminal TPLH and old biAT mice (age 15 months) but not in the brainstem of old biGT mice (15 months). (b) Immunohistochemistry with AT100 on free-floating sagittal sections of terminal mice shows tangles and neuropil threads in cortex and brainstem of all genotypes, but significantly less in the brainstem of biGT mice. Tauopathy is minimal or absent in pyramidal neurons of the hippocampus of terminal Tau.P301L transgenic mice.

Mentions: Phosphorylation of Tau.P301L in mouse brain is initially low even up to the age of 7 months at the epitopes defined by Mabs AT8 and AT180, although phosphorylation is detectable with probes AD2 and AT270 [89]. The disease-associated epitope AT100 was even completely absent at young age. In older Tau.P301L mice, phosphorylation of Tau increases leading to reduced affinity of the MT-binding and consequent delocation to soma and dendrites. The local aggregation into tangles and neuropil threads in terminal mice is demonstrated immunohistochemically with Mab AT100 and others, for example, MC1 and PHF1, and biochemically by hyperphosphorylated Tau in the sarkosyl-insoluble fraction (Figure 1) [89]. The development of the tauopathy becomes associated with motor problems, illustrated by clasping and rotarod performance even as early as age 7.5 months, because the hindbrain and particularly specified nuclei in the brainstem, for example, Koelliker-Fuse and raphe, are hit by the tauopathy.


Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease.

Crespo-Biel N, Theunis C, Van Leuven F - Int J Alzheimers Dis (2012)

Selected biochemical and pathological characteristics of transgenic mouse models. (a) Soluble and sarkosyl insoluble fractions of Tau (SInT) were isolated as described [10] and proteins separated by SDS-PAGE on 10% tris-glycine gels. After transfer to nitrocellulose membranes, proteins were immunoblotted with either anti-pS396 (Invitrogen, Carlsbad, CA) or HT7 (Innogenetics, Gent, Belgium). Phosphorylated human Tau (apparent Mr about 64 kDa) is evident in soluble fractions from forebrain and brainstem of all three genotypes. SInT is evident in forebrain and brainstem of terminal TPLH and old biAT mice (age 15 months) but not in the brainstem of old biGT mice (15 months). (b) Immunohistochemistry with AT100 on free-floating sagittal sections of terminal mice shows tangles and neuropil threads in cortex and brainstem of all genotypes, but significantly less in the brainstem of biGT mice. Tauopathy is minimal or absent in pyramidal neurons of the hippocampus of terminal Tau.P301L transgenic mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376502&req=5

fig1: Selected biochemical and pathological characteristics of transgenic mouse models. (a) Soluble and sarkosyl insoluble fractions of Tau (SInT) were isolated as described [10] and proteins separated by SDS-PAGE on 10% tris-glycine gels. After transfer to nitrocellulose membranes, proteins were immunoblotted with either anti-pS396 (Invitrogen, Carlsbad, CA) or HT7 (Innogenetics, Gent, Belgium). Phosphorylated human Tau (apparent Mr about 64 kDa) is evident in soluble fractions from forebrain and brainstem of all three genotypes. SInT is evident in forebrain and brainstem of terminal TPLH and old biAT mice (age 15 months) but not in the brainstem of old biGT mice (15 months). (b) Immunohistochemistry with AT100 on free-floating sagittal sections of terminal mice shows tangles and neuropil threads in cortex and brainstem of all genotypes, but significantly less in the brainstem of biGT mice. Tauopathy is minimal or absent in pyramidal neurons of the hippocampus of terminal Tau.P301L transgenic mice.
Mentions: Phosphorylation of Tau.P301L in mouse brain is initially low even up to the age of 7 months at the epitopes defined by Mabs AT8 and AT180, although phosphorylation is detectable with probes AD2 and AT270 [89]. The disease-associated epitope AT100 was even completely absent at young age. In older Tau.P301L mice, phosphorylation of Tau increases leading to reduced affinity of the MT-binding and consequent delocation to soma and dendrites. The local aggregation into tangles and neuropil threads in terminal mice is demonstrated immunohistochemically with Mab AT100 and others, for example, MC1 and PHF1, and biochemically by hyperphosphorylated Tau in the sarkosyl-insoluble fraction (Figure 1) [89]. The development of the tauopathy becomes associated with motor problems, illustrated by clasping and rotarod performance even as early as age 7.5 months, because the hindbrain and particularly specified nuclei in the brainstem, for example, Koelliker-Fuse and raphe, are hit by the tauopathy.

Bottom Line: Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions.The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments.Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Experimental Genetics Group (LEGTEGG), Department of Human Genetics, KU Leuven, Campus Gasthuisberg ON1-06.602, Herestraat 49, 3000 Leuven, Belgium.

ABSTRACT
The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis of a wide variety of brain-damaging disorders, known as tauopathies. These include Alzheimer's disease (AD), denoted as secondary tauopathy because of the obligatory combination with amyloid pathology. In all tauopathies, protein Tau becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate as threads in neuropil and as tangles in soma. The argyrophilic neurofibrillary threads and tangles, together denoted as NFT, provide the postmortem pathological diagnosis for all tauopathies. In AD, neurofibrillary threads and tangles (NFTs) are codiagnostic with amyloid depositions but their separated and combined contributions to clinical symptoms remain elusive. Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions. Conversely, the biochemical and pathological timeline is not exactly known in human tauopathy, but experimental models point to smaller Tau-aggregates, termed oligomers or multimers, as synaptotoxic in early stages. The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments. Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.

No MeSH data available.


Related in: MedlinePlus