MAPT Target Analysis Report Summary
About the Target
Based on the provided context information, here are some key viewpoints regarding the role of tau (MAPT) in Alzheimer's disease (AD):
In AD, the abnormal production of Amyloid beta (Aβ) peptides, triggered by the shedding of Amyloid precursor protein (APP), leads to the activation of GSK-3. This activation results in hyperphosphorylation of tau proteins, leading to the formation of neurofibrillary tangles (NFTs) and the destruction of microtubules, ultimately causing neuronal death [1].
Astrocytes and microglia are activated in response to Aβ and pro-inflammatory cytokines such as TNF-α. These activated cells produce various pro-inflammatory cytokines, promoting neuroinflammation in AD. Additionally, activated microglia and macrophages help in reducing Aβ deposits through endocytosis, while astrocytes secrete Aβ [1].
The NLRP3-ASC inflammasome, consisting of NLRP3, ASC, and pro-caspase 1, can be assembled by either fibrillary Aβ or tau species. Activation of this inflammasome results in the release of pro-inflammatory cytokines, including IL-1β and IL-18, and promotes neuronal tau hyperphosphorylation in a manner dependent on IL-1 receptor activation [2].
The CHIP p.Glu278fs mutation can lead to impaired degradation of alpha-synuclein and tau. Under normal conditions, CHIP targets misfolded proteins for proteasome degradation. However, in the presence of the mutation, the interaction between CHIP and its specific E2 ligase is disrupted, impairing CHIP's E3 ligase activity and potentially promoting the progression of ataxia [3].
Tau plays a role in regulating cargo delivery and fast axonal transport. In the normal conformation, a phosphatase-activation domain (PAD) in the N-terminal end of tau is not exposed, preventing the triggering of the PKC and cargo detachment from microtubules. Abnormal tau phosphorylation and hyperphosphorylation, often associated with GSK3 activation, result in the persistent exposure and activation of PAD, leading to impaired axonal transport and tau aggregation [4].
Tau phosphorylation has a significant impact on synaptic receptors, proteins, and structures, affecting synaptic function and contribute to AD pathogenesis [5].
These viewpoints provide a comprehensive summary of the role of tau in AD and highlight various aspects, including the interaction with Aβ, inflammation, degradation mechanisms, axonal transport disruption, and synaptic effects.
Based on the information provided, there are several key viewpoints related to MAPT (also known as Tau):
Tau phosphorylation at specific sites plays a crucial role in the stabilization of tau protein, and abnormal phosphorylation at Ser356 is associated with a more advanced stage of tau pathology compared to phosphorylation at Ser262 [7].
MAPT is influenced by DLX1/DLX2 genes, which may affect MAPT through the WNT or GABA signaling pathways [8].
Tau competes with CX3CL1 for binding to CX3CR1, a receptor involved in tau internalization, suggesting a potential interaction between tau and these receptors [9].
MAPT activation, particularly by ISOC, leads to calcium influx and subsequent binding of S100A6 to induce translocation of S100A6 to the plasma membrane. This interaction with FKBP51 and PPP5C results in tau isomerization and dephosphorylation, enabling binding to microtubules and promoting polymerization [10].
These viewpoints highlight different aspects of MAPT, including its phosphorylation, genetic regulation, interaction with receptors, and its role in microtubule binding and polymerization.
Figure [1]
Figure [2]
Figure [3]
Figure [4]
Figure [5]
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Figure [10]
Note: If you are interested in the full version of this target analysis report, or if you'd like to learn how our AI-powered BDE-Chem can design therapeutic molecules to interact with the MAPT target at a cost 90% lower than traditional approaches, please feel free to contact us at BD@silexon.ai.
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