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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

Schematic view of relations between amyloid and Tau in Alzheimer's disease. The interpretation hinges on the concept that the production of the Tau-P* intermediates are the central molecular species in the overall process. The incorporation of GSK3 as a major coupling link between the two pathologies is underscored essentially by in vivo observations in the mono- and bigenic mouse models discussed in the text. Protein Tau is a very soluble, naturally unfolded protein that in physiological conditions is located mainly in axons and attached to microtubules, denoted as Tau-MT. Activation by amyloid of both GSK3 kinases, together with other kinases including Mar2/Par1, gradually transforms Tau-MT into a pool of soluble, phosphorylated Tau (pTau) in the cytoplasm. Because of their delocalization, the pTau species undergo further posttranslational modifications, mainly including additional phosphorylation but eventually also nitrosylation, acetylation, truncation, all causing the transition into the conformational protein Tau species that we previously denoted as Tau-P* [11]. This as yet molecularly undefined intermediate likely represents soluble low-order aggregates that cause the early synaptic defects and cognitive problems typical for all tauopathies, with brain-region specificity as discussed in the text. The escape of Tau-P* from normal elimination via the proteasome and/or by autophagy leads to its accumulation, which by mass-action results in aggregation into NFT. We primarily consider NFT not to be detrimental for neurons, and initially they can even constitute a relative safety measure, as they reduce the free levels of Tau-P* and thereby its negative actions. Conversely, in the long term, the progressive accumulation of Tau-P* into more NFT deposition in neuropil and soma must invoke negative effects and eventually result in axonal and dendritic defects that culminate in neurodegeneration. This process is schematically reflected by the green-to-red color gradient of the background of the NFT box in the scheme.
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fig2: Schematic view of relations between amyloid and Tau in Alzheimer's disease. The interpretation hinges on the concept that the production of the Tau-P* intermediates are the central molecular species in the overall process. The incorporation of GSK3 as a major coupling link between the two pathologies is underscored essentially by in vivo observations in the mono- and bigenic mouse models discussed in the text. Protein Tau is a very soluble, naturally unfolded protein that in physiological conditions is located mainly in axons and attached to microtubules, denoted as Tau-MT. Activation by amyloid of both GSK3 kinases, together with other kinases including Mar2/Par1, gradually transforms Tau-MT into a pool of soluble, phosphorylated Tau (pTau) in the cytoplasm. Because of their delocalization, the pTau species undergo further posttranslational modifications, mainly including additional phosphorylation but eventually also nitrosylation, acetylation, truncation, all causing the transition into the conformational protein Tau species that we previously denoted as Tau-P* [11]. This as yet molecularly undefined intermediate likely represents soluble low-order aggregates that cause the early synaptic defects and cognitive problems typical for all tauopathies, with brain-region specificity as discussed in the text. The escape of Tau-P* from normal elimination via the proteasome and/or by autophagy leads to its accumulation, which by mass-action results in aggregation into NFT. We primarily consider NFT not to be detrimental for neurons, and initially they can even constitute a relative safety measure, as they reduce the free levels of Tau-P* and thereby its negative actions. Conversely, in the long term, the progressive accumulation of Tau-P* into more NFT deposition in neuropil and soma must invoke negative effects and eventually result in axonal and dendritic defects that culminate in neurodegeneration. This process is schematically reflected by the green-to-red color gradient of the background of the NFT box in the scheme.

Mentions: Therefore, both tangle formation and neuron loss should be considered as dissociated processes, at least in time, but likely also in actual underlying mechanisms (Figure 2). Direct assessment of the relation of tangles and neuronal function by electrophysiology of individual neurons ex vivo, concomitant with structural analysis of dendritic branching and spines, did not correlate with NFT bearing [125]. Similarly, the findings in mammalian models was also observed in invertebrate Tau models [126, 127]. The justified conclusion must be that other, less aggregated or even soluble forms of protein Tau are responsible for neuronal dysfunction and by extension for failing synaptic plasticity and cognition. More and more, NFTs are regarded to function as the intraneuronal sink for excess phosphorylated protein Tau that was released from the axonal microtubules and after delocalization and extra phosphorylation is unable to regain its normal physiological position and function. By forming large fibrillar aggregates, neurons are protected from toxic effects of soluble, smaller aggregates [128, 129], a mechanism that was even proposed as a potential therapeutic approach [130]. Obviously, the cytoplasmic sink is limited in capacity and this protective measure cannot but be limited in time, eventually resulting in the damage and death of the neuron, exemplified by the presence of ghost tangles in the later stages of tauopathy [16].


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)

Schematic view of relations between amyloid and Tau in Alzheimer's disease. The interpretation hinges on the concept that the production of the Tau-P* intermediates are the central molecular species in the overall process. The incorporation of GSK3 as a major coupling link between the two pathologies is underscored essentially by in vivo observations in the mono- and bigenic mouse models discussed in the text. Protein Tau is a very soluble, naturally unfolded protein that in physiological conditions is located mainly in axons and attached to microtubules, denoted as Tau-MT. Activation by amyloid of both GSK3 kinases, together with other kinases including Mar2/Par1, gradually transforms Tau-MT into a pool of soluble, phosphorylated Tau (pTau) in the cytoplasm. Because of their delocalization, the pTau species undergo further posttranslational modifications, mainly including additional phosphorylation but eventually also nitrosylation, acetylation, truncation, all causing the transition into the conformational protein Tau species that we previously denoted as Tau-P* [11]. This as yet molecularly undefined intermediate likely represents soluble low-order aggregates that cause the early synaptic defects and cognitive problems typical for all tauopathies, with brain-region specificity as discussed in the text. The escape of Tau-P* from normal elimination via the proteasome and/or by autophagy leads to its accumulation, which by mass-action results in aggregation into NFT. We primarily consider NFT not to be detrimental for neurons, and initially they can even constitute a relative safety measure, as they reduce the free levels of Tau-P* and thereby its negative actions. Conversely, in the long term, the progressive accumulation of Tau-P* into more NFT deposition in neuropil and soma must invoke negative effects and eventually result in axonal and dendritic defects that culminate in neurodegeneration. This process is schematically reflected by the green-to-red color gradient of the background of the NFT box in the scheme.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Schematic view of relations between amyloid and Tau in Alzheimer's disease. The interpretation hinges on the concept that the production of the Tau-P* intermediates are the central molecular species in the overall process. The incorporation of GSK3 as a major coupling link between the two pathologies is underscored essentially by in vivo observations in the mono- and bigenic mouse models discussed in the text. Protein Tau is a very soluble, naturally unfolded protein that in physiological conditions is located mainly in axons and attached to microtubules, denoted as Tau-MT. Activation by amyloid of both GSK3 kinases, together with other kinases including Mar2/Par1, gradually transforms Tau-MT into a pool of soluble, phosphorylated Tau (pTau) in the cytoplasm. Because of their delocalization, the pTau species undergo further posttranslational modifications, mainly including additional phosphorylation but eventually also nitrosylation, acetylation, truncation, all causing the transition into the conformational protein Tau species that we previously denoted as Tau-P* [11]. This as yet molecularly undefined intermediate likely represents soluble low-order aggregates that cause the early synaptic defects and cognitive problems typical for all tauopathies, with brain-region specificity as discussed in the text. The escape of Tau-P* from normal elimination via the proteasome and/or by autophagy leads to its accumulation, which by mass-action results in aggregation into NFT. We primarily consider NFT not to be detrimental for neurons, and initially they can even constitute a relative safety measure, as they reduce the free levels of Tau-P* and thereby its negative actions. Conversely, in the long term, the progressive accumulation of Tau-P* into more NFT deposition in neuropil and soma must invoke negative effects and eventually result in axonal and dendritic defects that culminate in neurodegeneration. This process is schematically reflected by the green-to-red color gradient of the background of the NFT box in the scheme.
Mentions: Therefore, both tangle formation and neuron loss should be considered as dissociated processes, at least in time, but likely also in actual underlying mechanisms (Figure 2). Direct assessment of the relation of tangles and neuronal function by electrophysiology of individual neurons ex vivo, concomitant with structural analysis of dendritic branching and spines, did not correlate with NFT bearing [125]. Similarly, the findings in mammalian models was also observed in invertebrate Tau models [126, 127]. The justified conclusion must be that other, less aggregated or even soluble forms of protein Tau are responsible for neuronal dysfunction and by extension for failing synaptic plasticity and cognition. More and more, NFTs are regarded to function as the intraneuronal sink for excess phosphorylated protein Tau that was released from the axonal microtubules and after delocalization and extra phosphorylation is unable to regain its normal physiological position and function. By forming large fibrillar aggregates, neurons are protected from toxic effects of soluble, smaller aggregates [128, 129], a mechanism that was even proposed as a potential therapeutic approach [130]. Obviously, the cytoplasmic sink is limited in capacity and this protective measure cannot but be limited in time, eventually resulting in the damage and death of the neuron, exemplified by the presence of ghost tangles in the later stages of tauopathy [16].

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