Abstract
In humans, a considerable number of the autopsy samples of cognitively normal individuals aged between 57 and 102 years have revealed the presence of amyloid plaques, one of the typical signs of AD, indicating that many of us use mechanisms that defend ourselves from the toxic consequences of Aß. The human APP NL/F (hAPP NL/F) knockin mouse appears as the ideal mouse model to identify these mechanisms, since they have high Aß42 levels at an early age and moderate signs of disease when old. Here we show that in these mice, the brain levels of the hemoprotein Neuroglobin (Ngb) increase with age, in parallel with the increase in Aß42. In vitro, in wild type neurons, exogenous Aß increases the expression of Ngb and Ngb over-expression prevents Aß toxicity. In vivo, in old hAPP NL/F mice, Ngb knockdown leads to dendritic tree simplification, an early sign of Alzheimer’s disease. These results could indicate that Alzheimer’s symptoms may start developing at the time when defense mechanisms start wearing out. In agreement, analysis of plasma Ngb levels in aged individuals revealed decreased levels in those whose cognitive abilities worsened during a 5-year longitudinal follow-up period.
Highlights
Numerous studies in different experimental settings demonstrate the direct association between an excess of oligomeric forms of Aβ peptide and the appearance of some of the pathological signs characteristics of Alzheimer’s disease (AD) (Walsh et al, 2002; Li et al, 2009; Dinamarca et al, 2012)
We did not detect significant changes in proteasomal function (Supplementary Figure S2A), nor in protein stress response (Supplementary Figure S2B), which are found elevated in AD patients (Lukiw, 2004)
Detect an increase in the number of reactive astrocytes compared to age-matched WT mice (Supplementary Figure S3A) and an increase in the levels of tau phosphorylation at the pathogenic epitope Pair Helical Filament-1 (PHF1) (Supplementary Figure S3B)
Summary
Numerous studies in different experimental settings demonstrate the direct association between an excess of oligomeric forms of Aβ peptide and the appearance of some of the pathological signs characteristics of Alzheimer’s disease (AD) (Walsh et al, 2002; Li et al, 2009; Dinamarca et al, 2012). In sporadic forms of AD, increased Aβ levels are detected in plasma-derived neuronal exosomes up to 10 years before the manifestation of the first symptoms (Fiandaca et al, 2015) All these data imply the existence of robust resilience mechanisms, such as the recently identified PLA2 G4E (Perez-Gonzalez et al, 2020), counteracting the detrimental effect of different toxicity factors, including excessive production of the more damaging forms of Aβ peptide. The identification of these mechanisms is a fundamental process if we want to prevent or cure this disease
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