Acta Neuropathologica: A multifaith pathology model of heterogeneity at the age of onset of familial Alzheimer's disease

Dementia refers to chronic access to carrying out intelligent disorder syndrome, which is often characterized by slow-onset intelligent decline.
age-related dementia, such as Alzheimer's disease (AD), is a growing burden on modern society.
AD has a wide range of clinical characteristics, according to AD's amyloid hypothesis, the production and aggregation of β-amyloid peptides (A beta) are the initiators and main factors of a series of events, including oxidative stress, synaptic dysfunction, mitochondrial dysfunction and neurodegenerative changes caused by excessive phosphateization of Tau protein (pTau).
all family AD (FAD) disease-caused mutations in early ethyretin 1 (PSEN1), early ethyretin 2 (PSEN2) and amyloid preload protein (APP) are associated with the production or aggregation of A-beta, which is one of the main arguments in support of the amyloid hypothesis.
mutations in PSEN1 and PSEN2 are beneficial for the production of aggregated A-beta peptides.
the fact that the length and ratio of A-beta peptides changed in PESN1 FAD brain tissue, cell culture, and mouse models reinforced the concept of their contribution to FAD pathophysiology.
test examined the brains of 23 patients, focusing on the production and deposition of β-amyloid protein (A beta) and the pathological characteristics of Tau.
in 14 patients with early onset age (AoO) extremes, the study conducted a full-scale exon capture to determine the genotype-esotype correlation.
we also studied peptide group activity, protease activity, and protein polysulphation in brain tissue and associated it with the Tau phosphatization spectrum.
AoO in patients with PSEN1-E280A was twin peaks.
except AoO, there were no clinical differences between the groups.
, although the mutant PSEN1 has an effect on the production of A-beta, there is no associated difference between groups in the production and deposition of A-beta.
, however, differences were found in the pathology of highly phosphatized Tau (pTau), where early-oncrills patients showed severe pathology of diffuse aggregation patterns associated with increased stress kinase activation.
patients showed less pTau pathology and unique kinase activity.
addition, the study also found new protective gene variants that affect the function of ubibin-proteases in early-oncrill patients, resulting in higher ubibin-dependent degradation of differential phosphate Tau.
in PSEN1-E280A carriers, changes in γ-secretion enzyme activity and the accumulation of A-beta are prerequisites for early AoO.
, however, the excessive phosphatization pattern of Tau protein and its degradation by proteases greatly affect the incidence of disease in individuals with A-beta pathology, suggesting a multifaceted disease model of FAD.
, the heterogeneity induced by Tau is a common feature of the two AD variants, suggesting that AD can be treated with multi-target therapy.
Sepulveda-Falla, D., Chavez-Gutierrez, L., Portelius, E. et al. A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer’s disease. Acta Neuropathol (2020). Network Source: Network Copyright Notice: All text, images and audio and video materials on this website that indicate "Source: Met Medical" or "Source: MedSci Original" are owned by Metz Medicine and are not authorized to be reproduced by any media, website or individual, and are authorized to be reproduced with the words "Source: Mets Medicine".
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