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- W2897953320 abstract "The cognitive decline during Alzheimer's disease (AD) is caused by the progressive synaptic and neuronal loss in hippocampus and various cortical regions. Accumulation and aggregation of Aβ peptides as well formation of insoluble tau tangles is strongly associated with AD pathology. However, the exact molecular mechanisms of Aβ and tau driven neurodegeneration remain elusive, particularly for the early stage of the disease. We performed the age-dependent proteome analysis of soluble brain fraction of 3xTg-AD (PSEN M146V, APP Swe, MAPT P301L) and control mice at four distinct time points (2, 6, 12 and 18 months of age) that correspond to various stages of the disease progression. Expression of significantly up and down regulated proteins was validated by immunoblotting and immunohistochemistry. Expression of selected identified presymptomatic markers of the disease (significantly regulated at time point 2 months) was assessed in human postmortem brain samples obtained from slowly (n = 8) and rapidly (n = 8) progressing AD cases and age-matched healthy controls (n = 9). The brain proteome of 3xTg-AD mice undergoes a progressive remodeling along the development of the disease. Several protein groups demonstrated a coordinated pattern of expression change across the disease progression. These were the proteins involved in mRNA processing and splicing, neuroinflammation, regulation of protease activity and myelin organization. Our analysis revealed a novel candidate Heme binding protein-1 (Hebp1) that was strongly upregulated in young 3xTg-AD mice even before manifestation of any AD symptoms and remained upregulated for the full duration of the disease. We could also confirm the elevated expression of Hebp1 in rapidly-progressing human AD cases. Immunohistochemical analysis revealed that Hebp1 is predominantly a neuronal protein. Knock-out of Hebp1 in HeLa cells reduced cell death upon treatment with hemin indicating that Hebp1 is required to sensitize cells to heme-mediated toxicity. We develop a proteome map of AD progression in 3xTg-AD model and identify Hebp1 as a novel protein involved in AD. Hebp1 plays a role in early pathological events and is linked to cell death." @default.
- W2897953320 created "2018-10-26" @default.
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- W2897953320 date "2018-07-01" @default.
- W2897953320 modified "2023-10-16" @default.
- W2897953320 title "P2‐201: DECIPHERING THE PROGRESSION OF ALZHEIMER'S DISEASE BY PROTEOMIC ANALYSIS" @default.
- W2897953320 doi "https://doi.org/10.1016/j.jalz.2018.06.889" @default.
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