DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice
Introduction
The cause of Alzheimer's disease (AD) is still largely unknown despite many years of extensive research. Since AD is characterized by the presence of neurofibrillary tangles and amyloid-β (Aβ) containing aggregates in neuritic plaques and cerebral blood vessel walls, it has been suggested that accumulation of cerebral Aβ is the primary influence driving AD pathogenesis (the amyloid-β hypothesis; Selkoe, 2002). However, gene mutations in presenilin 1 (PS1), presenilin 2 (PS2), or amyloid precursor protein (APP) responsible for increased production of Aβ (Selkoe and Schenk, 2003), are only responsible for approximately 5% of all cases of AD worldwide. Therefore, it could be suggested that beside Aβ, other AD risk factors such as cardiovascular-, lifestyle- or environmental factors, play an important role in the development of AD (Breteler, 2000, Dosunmu et al., 2007, Meyer et al., 1998).
There are indications that modification of lifestyle factors, such as nutrition, alter the risk of developing AD later in life (Dosunmu et al., 2007, Gillette Guyonnet et al., 2007). For example, high serum cholesterol, which can be caused by dietary intake, is an important risk factor in AD (Kivipelto et al., 2002, Kivipelto et al., 2001). The role of cholesterol in AD is also strengthened by epidemiological studies that associate cholesterol lowering statins with diminished prevalence of AD (Jick et al., 2000) and with less deterioration of cognitive functions (Sparks et al., 2005). Identification of the cholesterol transporter apolipoprotein E4 as a major genetic risk factor for hypercholesterolemia, vascular dementia and sporadic AD (Corder et al., 1994, Poirier et al., 1993, Strittmatter et al., 1993), has reinforced the relationship between cholesterol and AD. Further support comes from cell culture and experimental animal studies. For example, reduction of cellular cholesterol levels in rat hippocampal neurons reduce the formation of Aβ (Simons et al., 1998), whereas high dietary cholesterol intake in double transgenic AD mice increases Aβ accumulation (Hooijmans et al., 2007b, Refolo et al., 2000). In addition, a study in guinea pigs showed that lowering whole body cholesterol with statins decreases Aβ formation (Fassbender et al., 2001).
Another lipid diet factor influencing the risk of AD is the omega-3 long chain poly-unsaturated fatty acid (n-3 lc-PUFA) docosahexenoic acid (DHA). The Framingham Heart study showed that people with high plasma DHA levels have a decreased risk of developing AD (Schaefer et al., 2006). Also other epidemiological studies have indicated that sufficient DHA intake reduces the risk of developing AD (Barberger-Gateau et al., 2002, Kalmijn et al., 1997b, Morris et al., 2003). Several studies have shown that dietary intake of n-3 PUFA may reduce cognitive decline (Kotani et al., 2006, van Gelder et al., 2007), and a recent trial by Freund-Levi et al. (2006) showed positive effects of DHA supplementation on cognition in patients with very mild AD. Recent experimental studies in APP transgenic mice reported decreased brain Aβ levels after dietary DHA supplementation (Lim et al., 2005, Oksman et al., 2006). It has been proposed that DHA supplementation increases the amount of the neuronal sorting protein LR11 which regulates APP processing together with a subsequent decrease in Aβ production (Ma et al., 2007). In addition, Calon et al. (2004) showed that DHA supplementation to DHA depleted tg2576 AD mice improved memory acquisition. Taken together, the above-mentioned data show that high cholesterol levels or low plasma DHA levels are risk factors for AD. Moreover, cholesterol and DHA are also involved in cardiovascular diseases such as hypertension and atherosclerosis (Skoog and Gustafson, 2006). It could therefore be suggested that cholesterol and DHA may also exert their effects on the development of AD by influencing the peripheral and cerebral vasculature. A recent study performed in our lab, showed that a cholesterol enriched Typical Western Diet (TWD) and a DHA diet, indeed, influenced cerebral hemodynamics such as the cerebral blood volume (CBV) in 18-month-old double transgenic APP/PS1 mice (Hooijmans et al., 2007b). This is in line with studies showing that CBV is affected in AD (Harris et al., 1998). In addition a study from Niwa et al. (2002) showed that in Tg2576 Alzheimer mice cerebral blood flow (CBF) was reduced throughout the brain prior to Aβ deposition, suggesting that cerebrovascular abnormalities are early events in the pathogenesis of Alzheimer's disease.
Our study also showed that the cholesterol enriched TWD diet increased plaque burden in the hippocampus, whereas the DHA-enriched diet decreased the amount of Aβ deposits in cerebral blood vessel walls in the 18-month-old double transgenic APP/PS1 mice (Hooijmans et al., 2007b).
In the current study we investigate whether changes in the relative cerebral blood volume (rCBV), determined using susceptibility enhanced MRI, would precede changes in Aβ deposition in these APP/PS1 mice or vice versa. We also tested the effects of DHA and TWD diets on cognition, rCBV, the amount of Aβ depositions and the sterol and fatty acid profiles of the brain, from 8- and 15-month-old APP/PS1 mice. We used similar diets as in our former study (Hooijmans et al., 2007b). Explorative behavior was determined with an open field test, and spatial learning and memory with both the Morris water maze (MWM), and the 12 circular hole board in 8- and 15-month-old wild type and double transgenic APPswe/PS1dE9 mice.
Section snippets
Animals and diets
The APPswe/PS1dE9 founders were obtained from Johns Hopkins University, Baltimore, MD, USA (D. Borchelt and J. Jankowsky, Dept. of Pathology) and a colony was established at the Radboud University Nijmegen Medical Center, The Netherlands. In short, mice were created by co-injection of chimeric mouse/human APPswe (mouse APP695 harboring a human Aβ domain and mutations K595N and M596L linked to Swedish familial AD pedigrees) and human PS1-dE9 (deletion of exon 9) vectors controlled by independent
Body and brain weight
All mice were weighed 1 week before starting the behavioral test battery. Body weight was not affected by genotype or diet at either 8 months or 15 months. Overall mean body weight was 32.4 ± 0.4 g in the 8-month-old mice and 44.0 ± 0.6 g in the 15-month-old group. Relative brain weight was not affected by genotype or diet in both 8- and 15-month-old mice. Overall mean brain weight was 1.60 ± 0.03% of total body weight in the 8-month-old mice and 1.17 ± 0.03% in the 15-month-old group. Absolute brain
Discussion
The present data show that the DHA-enriched diet altered rCBV in 8-month-old APP/PS1 and wild type mice[AU1]. In addition, 15-month-old APP/PS1 mice fed DHA-enriched diet for more than a year showed improved spatial memory, decreased parenchymal and vascular Aβ in the brain and a slightly increased relative cerebral blood volume (rCBV), indicating that a DHA-enriched diet may diminish aggravation of Alzheimer-like pathology. In contrast, a TWD diet may increase AD development by decreasing the
Disclosure statement
- 1.
All authors (CR Hooijmans, PJWC Dederen, CEEM van der Zee, KM Brouwer, YD Reijmer, T van Groen, LM Broersen, D Lütjohann, A Heerschap and AJ Kiliaan) state that:
- a)
there are no actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within 3 years of beginning the work submitted that could inappropriately influence (bias) the work.
- b)
No institution has contracts relating to this research through which it or any other
Acknowledgments
We would like to thank Henk Arnts for his excellent care giving of our animals, Erna Basten en Coen Graven for their laboratory work, and Giulio Gambarota and Andor Veltien for their support with the MRI measurements. The laboratory work on sterol analyses of Sylvia Friedrichs from the Institute of Clinical Chemistry and Pharmacology, University of Bonn, Germany, is also gratefully acknowledged. Martin Balvers at Numico Research, Wageningen, skillfully performed all FA analyses. This study is
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