Evidences path(MESH:"Alzheimer Disease") to a(CHEBI:"amyloid-beta")

Staining for amyloid-β in the brains of nine patients with Alzheimer’s disease and eight controls without Alzheimer’s disease (Extended Data Table 1) revealed, as expected, marked parenchymal deposition of amyloid-β in the brains of patients with Alzheimer’s disease, but not in the brains of the controls without Alzheimer’s disease (Extended Data Fig. 9l, m)

Notably, when compared to tissue from controls, all samples from patients with Alzheimer’s disease demonstrated striking vascular amyloid-β pathology in the cortical leptomeninges (Extended Data Fig. 9l, m) and amyloid-β deposition in the dura mater adjacent to the superior sagittal sinus (Fig. 3i, j) or further away from the sinus (Fig. 3k, l)

These findings showed that prominent meningeal amyloid-β deposition observed in patients with Alzheimer’s disease is also observed in mouse models of Alzheimer’s disease after meningeal lymphatic vessel ablation

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011).

Amyloid hypothesis is supported by the fact that progressive Aβ deposition is observed in early, preclinical stages of AD and, finally, in all AD patients.

An increasing ratio of the full-length, 1–42 peptide to the 1–40 form is associated with disease (Kumar-Singh et al., 2006), and mutations underlying familial forms of AD either increase this ratio or increase the amount of Abeta secreted.

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001).

With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010)

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game.

However, their dysfunction in AD due to some factors will reduce Aβ clearance

However, recently, it has been reported that the expression and transport activity of P-gp are impaired in sporadic AD as a result of its ubiquitination, internalization, and proteasome-dependent degradation derived from Aβ40 (Chiu et al. 2015; Hartz et al. 2016), which will result in Aβ deposition

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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.