Achucarro Seminars

15 Nov [2019]

at 13.00 CET

The role of the imbalance between aging-linked alterations and resilience mechanisms in Alzheimer's disease

Francesc X. Guix Ràfols

Severo Ochoa Molecular Biology Center (CBMSO), Madrid, Spain


According to the amyloid cascade hypothesis, the aggregation of amyloid-beta peptide (Ab) in the brain of Alzheimer patients triggers a series of downstream molecular events, including tau protein aggregation, which lead to neurodegeneration. Aging is known to be the first risk factor for Alzheimer's disease (AD), however it is not sufficient to cause the disease. Thus, while aging must be inducing molecular alterations in the brain that predisposes to AD, including the accumulation of Ab aggregates, the activation of resilience mechanisms in some individuals that counteracts these alterations might prevent the onset of symptoms. In order to advance our understanding of the resilience mechanisms against Ab toxicity, the human APP NL/F (hAPP NL/F) knockin mice, considered as a good preclinical AD model, was studied.  Despite the fact that these mice have high Aß42 levels, only mild pathological signs are observed when old. It was found that in parallel with the age-associated rise in Aß42 there is an increase in the levels of the brain-specific hemoprotein Neuroglobin (NGB).  In vitro experiments revealed that exogenous Aß increases the expression of NGB and that NGB over-expression prevents oxidative stress-mediated Aß toxicity. In vivo, NGB knockdown in hAPP NL/F mice, results in the appearance of neurons with reduced dendritic complexity, a well-documented early event in the course of AD. Finally, during the last years I tried to understand those aging-linked molecular alterations that contribute to AD. The results of this research revealed the role of aging-associated nitrosative stress in the generation of toxic Aß species and the release of higher number of exosomes by old neurons due to endosomal cholesterol accumulation. Exosomes could contribute to AD pathology by: i) spreading pathological forms of tau throughout the brain of AD patients; ii) spreading toxic Ab oligomers in the brain and iii) contributing to neuroinflammation by activating the microglia.

Host: Estibaliz Capetillo

This seminar is partially supported by the Campus of Biscay of the UPV/EHU.