Cerebrovascular β‐amyloid deposition and associated microhemorrhages in a Tg2576 Alzheimer mouse model are reduced with a DHA‐enriched diet

Abstract

Cerebral amyloid angiopathy (CAA) is a major contributor to Alzheimer's disease (AD) pathogenesis. Like AD, CAA is often accompanied by marked inflammation, aggravating associated vasculopathies. No evidence-based prevention or treatment strategies are available. Here, we evaluate the possible beneficial effect of a diet enriched with docosahexaenoic acid (DHA), which is known to attenuate inflammation in CAA. Tg2576 mice, a transgenic model of AD/CAA, were fed a DHA-enriched diet starting at 2 mo of age and ending at 10, 14, or 18 mo of age. β-Amyloid (Aβ)-peptide deposition and bleeding were visualized by immunohistochemistry or histochemistry on coronal sections of the brain. DHA, arachidonic acid, and eicosanoid levels were measured by liquid chromatography/mass spectrometry or GC-MS. DHA-enriched diet throughout aging limits the accumulation of vascular Aβ peptide deposits as well as the likelihood of microhemorrhages. There is a strong correlation between systemic 12-hydroxyeicosatetraenoic acid (HETE) levels and the size of the area affected by both vascular amyloid deposits and hemorrhages. The lowest levels of 12-HETE, a lipid-derived proinflammatory product of 12-lipoxygenase (LOX), were found in DHA-fed mice. In vitro experiments performed on amyloid vascular smooth muscle cells showed that a 12-LOX inhibitor almost completely blocked the Aβ peptide-induced apoptosis of these cells. This study yet again highlights the important role of inflammation in CAA pathogenesis and identifies potential new targets for preventive care.-Hur, J., Mateo, V., Amalric, N., Babiak, M., Béréziat, G., Kanony-Truc, C., Clerc, T., Blaise, R., Limon, I. Cerebrovascular β-amyloid deposition and associated microhemorrhages in a Tg2576 Alzheimer mouse model are reduced with a DHA-enriched diet.

Identification of bioactive metabolites using activity metabolomics

“…On an organ level, metabolites control pathophysiological reactions such as asthma via leukotrienes 121 . In complex organisms, nutritional interventions such as supplementation of omega-3 fatty acids proved to have multiple benefits, while lacking severe side effects 122,123 , and a plethora of studies has analyzed the phenotypic modulations evoked by feeding various supplemented diets to model organisms of ageing-associated diseases 124–126…”

Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications

“…The impact of 12/15-LOX is not limited to the peripheral nervous system, but also appears to play a strong role in the development of several central nervous system diseases. Interestingly, the 12/15-LOX pathway has been recently implicated in Alzheimer's disease (Hur et al, 2018;Pratico et al, 2004;Lebeau et al, 2001;Lebeau et al, 2004). There is also compelling data for the involvement of 12/15-LOX in brain damage due to stroke (Jin et al, 2008;Liu et al, 2017;van Leyen et al, 2006;van Leyen et al, 2014;Yigitkanli et al, 2013;Yigitkanliet al, 2017).…”

Characterization of the unique In Vitro effects of unsaturated fatty acids on the formation of amyloid β fibrils

“…Several in vivo studies in APP transgenic mice have shown that the supplementation of docosahexaenoic acid (DHA, 22:6), an ω-3 fatty acid rich in the brain, ameliorates cognitive dysfunction [13, 14, 15], Aß pathology [13–14, 16–23], or tau pathology [15, 18, 24]. It has also been reported that DHA inhibits in vitro Aß aggregation [25, 26], Aß production [16, 22, 27–29], or Aß toxicity in SH-SY5Y cells [26], primary neurons [30] or induced pluripotent stem cells derived from AD patients [31].…”