Evaluating the link between Paraoxonase-1 levels and Alzheimer's disease development

Abstract

At present, the etiopathogenesis of Alzheimer's disease (AD), the most common form of dementia, remains far to be fully deciphered. In the recent years, also the centrality of amyloid-β peptide in the pathogenesis of the neurodegenerative disease has been questioned and other hypotheses have been advanced. Notably, a common denominator of many of these theoretical models is represented by oxidative stress, which is widely proposed to play a role in the disease initiation and/or progression. Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme that endows its carrier with multiple biological functions, including the ability to contrast oxidative damage to lipid components of lipoproteins and cells and protect from toxicity of specific organophosphorus pesticides. The peculiar multi-functionality nature of PON1 might be the key for explaining the vast epidemiological data showing a close association between low serum PON1 activity and risk of several diseases, including cardiovascular and neurodegenerative diseases, in particular AD. In this review, we discuss the possible link between PON1 with AD pathogenesis and we hypothesize eventual mechanistic pathways that could account from epidemiological observations. We also highlight the methodological issue limitation in PON1 studies that still impede to give a definitive and certain picture of its effective biological impact on human health including AD.

Figure 1:. Serum arylesterase (ARE) levels patients with multiple sclerosis (MS), mild cognitive impairment (MCI), mixed dementia (MD), vascular dementia (VAD) or late onset Alzheimer disease (LOAD), were significantly lower compared to a control population.

Horizontal bars indicate medians and error bars correspond to interquartile range. Probability (p) for pairwise comparison were calculated by Bonferroni post-hoc test.

Figure 2.. Link between altered PON1 activity and AD development

This HDL-associated protein appear to play a role in the metabolism of cholesterol, by promoting the inverse cholesterol transport, and in the protection from oxidative challenges and pro-inflammatory challenges.^, Moreover, PON1 has been shown to protect our body from the adverse effects of OP pesticides that are considered a risk factors for AD.^, The finding that PON1 is also expressed in the brain further support the idea of an implication of PON1 in AD pathogenesis and this parallel with ours and other researchers work that have shown how the decreased serum levels of PON1 activity is linked to and increased risk of developing AD, and MCI, i.e. the so-called prodromal stage of the disease.^,,,