DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice

Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, (department: Anatomy and Cognitive Neuroscience) Geert Grooteplein noord 21, PO BOX 9101, 6500 HB, Nijmegen, The Netherlands.
Neurobiology of Disease (Impact Factor: 5.08). 03/2009; 33(3):482-98. DOI: 10.1016/j.nbd.2008.12.002
Source: PubMed


Cholesterol and docosahexenoic acid (DHA) may affect degenerative processes in Alzheimer's Disease (AD) by influencing Abeta metabolism indirectly via the vasculature. We investigated whether DHA-enriched diets or cholesterol-containing Typical Western Diets (TWD) alter behavior and cognition, cerebral hemodynamics (relative cerebral blood volume (rCBV)) and Abeta deposition in 8- and 15-month-old APP(swe)/PS1(dE9) mice. In addition we investigated whether changes in rCBV precede changes in Abeta deposition or vice versa. Mice were fed regular rodent chow, a TWD-, or a DHA-containing diet. Behavior, learning and memory were investigated, and rCBV was measured using contrast-enhanced MRI. The Abeta load was visualized immunohistochemically. We demonstrate that DHA altered rCBV in 8-month-old APP/PS1 and wild type mice[AU1]. In 15-month-old APP/PS1 mice DHA supplementation improved spatial memory, decreased Abeta deposition and slightly increased rCBV, indicating that a DHA-enriched diet can diminish AD-like pathology. In contrast, TWD diets decreased rCBV in 15-month-old mice. The present data indicate that long-term dietary interventions change AD-like pathology in APP/PS1 mice. Additionally, effects of the tested diets on vascular parameters were observed before effects on Abeta load were noted. These data underline the importance of vascular factors in the APP/PS1 mouse model of AD pathology.

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    • "Indeed, markers of AD neuropathology are sensitive to n-3 PUFA in the CNS. A high n-3 PUFA content in brain tissue is associated with reduced Aβ levels [117] [118], reduced soluble hyperphosporylated tau [103] [117] [119], higher synaptic marker levels [120] [121] [122] and improved cognitive performance [103] [120] [123] in animal models of AD. Thus, ApoE4 could impact AD pathogenesis by decreasing circulating DHA concentrations or by interfering with its transport in the brain (Fig. 1). "
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    ABSTRACT: A brief overview of the evidence for omega-3 fatty acids and, in particular, of docosahexaenoic acid (DHA), involvement in cognition and in dementia is given. Two studies are presented in this regard in which the key intervention is a DHA supplement. The fist, the MIDAS Study demonstrated that DHA can be of benefit for episodic memory in healthy adults with a mild memory complaint. The second, the ADCS AD trial found no benefit of DHA in the primary outcomes but found an intriguing benefit for cognitive score in ApoE4 negative allele patients. This leads to a consideration of the mechanisms of action and role of ApoE and its modulation by DHA. Given the fundamental role of ApoE in cellular lipid transport and metabolism in the brain and periphery, it is no surprise that ApoE affects n-3 PUFA brain function as well. It remains to be seen to what extent ApoE4 deleterious effect in AD is associated with n-3 PUFA-related cellular mechanisms in the brain and, more specifically, whether ApoE4 directly impairs the transport of DHA into the brain, as has been suggested.
    Prostaglandins Leukotrienes and Essential Fatty Acids 10/2014; 92. DOI:10.1016/j.plefa.2014.10.003 · 2.35 Impact Factor
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    • "Insufficient amounts of cholesterol may interrupt essential processes such as myelin formation, synaptic transmission and cognitive ability in mice [78] [79], while a reduction in oxysterols has been shown to correlate with the severity of dementia and brain atrophy [9] [10] [80]. Interestingly , 8-month old A␤PP Swe /PS1E9 mice on a pure C57BL/6J background did not demonstrate significantly different levels of cholesterol, while 15-month old transgenic mice had significantly lower cholesterol levels compared to control mice [81]. It is noteworthy that decreased levels of cholesterol in cerebral spinal fluid and plasma have been found in patients with AD [11] [12]. "
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    ABSTRACT: Impairments in cognitive ability and widespread pathophysiological changes caused by neurotoxicity, neuroinflammation, oxidative damage, and altered cholesterol homeostasis are associated with Alzheimer's disease (AD). Cannabidiol (CBD) has been shown to reverse cognitive deficits of AD transgenic mice and to exert neuroprotective, anti-oxidative, and anti-inflammatory properties in vitro and in vivo. Here we evaluate the preventative properties of long-term CBD treatment in male AβPPSwe/PS1ΔE9 (AβPP × PS1) mice, a transgenic model of AD. Control and AD transgenic mice were treated orally from 2.5 months of age with CBD (20 mg/kg) daily for 8 months. Mice were then assessed in the social preference test, elevated plus maze, and fear conditioning paradigms, before cortical and hippocampal tissues were analyzed for amyloid load, oxidative damage, cholesterol, phytosterols, and inflammation. We found that AβPP × PS1 mice developed a social recognition deficit, which was prevented by CBD treatment. CBD had no impact on anxiety or associative learning. The prevention of the social recognition deficit was not associated with any changes in amyloid load or oxidative damage. However, the study revealed a subtle impact of CBD on neuroinflammation, cholesterol, and dietary phytosterol retention, which deserves further investigation. This study is the first to demonstrate CBD's ability to prevent the development of a social recognition deficit in AD transgenic mice. Our findings provide the first evidence that CBD may have potential as a preventative treatment for AD with a particular relevance for symptoms of social withdrawal and facial recognition.
    Journal of Alzheimer's disease: JAD 07/2014; 42(4). DOI:10.3233/JAD-140921 · 4.15 Impact Factor
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    • " is known that a number of dietary changes such as high fat , high cholesterol , high trans fatty acid diets and thi - amine deficiency are amyloidogenic , while calorie restriction , increased dietary copper levels and docosahexanoic acid supplementation reduce Ab production ( Levin - Allerhand et al . 2002 ; Ho et al . 2004 ; Wang et al . 2005 ; Hooijmans et al . 2009 ; Zhao et al . 2011 ) . Moreover , environmental enrichment that is associated with increased cognitive and physical stimulation is known to reduce Ab plaque forma - tion in the mouse ( Calderon - Garcidue~ nas et al . 2004 ; Her - ring et al . 2011 ) . Our finding of tubular aggregates in both wild - type and transgenic animals are con"
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    ABSTRACT: The aim of this study is to determine whether primary over-expression of AβPP in skeletal muscle results in the development of features of inclusion body myositis (IBM) in a new lineage of the MCK-AβPP transgenic mouse. Quantitative histological, immunohistochemical and western blotting studies were performed on muscles from 3 to 18 month old transgenic and wild-type C57BL6/SJL mice. Electron microscopy was also performed on muscle sections from selected animals. Although western blotting confirmed that there was over-expression of full length AβPP in transgenic mouse muscles, deposition of amyloid-β and fibrillar amyloid could not be demonstrated histochemically or with electron microscopy. Additionally, other changes typical of IBM such as rimmed vacuoles, cytochrome C oxidase-deficient fibres, upregulation of MHC antigens, lymphocytic inflammatory infiltration and T cell fibre invasion were absent. The most prominent finding in both transgenic and wild-type animals was the presence of tubular aggregates which was age-related and largely restricted to male animals. Expression of full length AβPP in this MCK-AβPP mouse lineage did not reach the levels required for immunodetection or deposition of amyloid-β as in the original transgenic strains, and was not associated with the development of pathological features of IBM. These negative results emphasise the potential pitfalls of re-deriving transgenic mouse strains in different laboratories.
    International Journal of Experimental Pathology 12/2013; 94(6):418-25. DOI:10.1111/iep.12048 · 2.17 Impact Factor
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