Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models
Introduction
Diet strongly influences the incidence and outcome in major age-related diseases including diabetes, obesity, and vascular disease. Recent findings extend influences of diet to Alzheimer disease (AD) [8], [13], [16], [18]. Obesity is also a risk factor for AD [12], [26], [28]. Animal models support these associations: brain amyloid is increased by cholesterol-rich diets to AD-transgenic mice [29], [32], dogs [10], and rabbits [33].
An opposite paradigm is caloric restriction (CR) which reduces body fat and increases life span while slowing many aging processes [14], including normal aging changes in the brain [17], [19], [20], [23]. CR in laboratory animals diminishes the apparent escalation of neuroinflammation and oxidative stress during aging by decreasing both glial activation and the production of reactive oxygen species [17], [20], [24]. Moreover, CR shows remarkable neuroprotective effects in young rodent models of neurodegenerative disease [4], [19]. For example, as little as 2 months of CR is neuroprotective for excitotoxic and metabolic insults [4]. Since pathogenesis of AD involves activated glia, increased oxidative damage and reduced neuroprotection, we tested whether CR of AD-transgenic mice can attenuate AD-like pathology, with a focus on Aβ deposits and glial activation. In AD, most Aβ-plaques are surrounded by activated astrocytes and microglia, which are thought to secrete numerous cytokines, complement factors and other inflammation-related proteins and which may contribute to neuroinflammatory and oxidative processes in AD pathology [1]. However, glial activation also occurs during normal aging in humans [21], [23], [31]. Glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, increases relatively early in adult life with progressive increases during aging [20], [23]. To avoid confounds of normal aging processes with AD-processes, we chose two transgenic models with early onset amyloid by age of 6 months: APPswe/ind (J20 line) mice with the double “Swedish” and “Indiana” APP mutations [22] and the doubly transgenic APP + PS1 mice [15].
Section snippets
APPswe/ind and caloric restriction
The APPswe/ind (J20 line) transgenic mice express human APP with the K670N/M671L “Swedish” and the V717F “Indiana” mutations under the PDGF promoter[22]. Male virgin mice carrying the transgene were separated into two groups—ad libitum (AL) and calorie-restricted (CR). Starting at 14–15 weeks of age, the CR group was gradually ramped down over a 4-week period from 5 to 3 g/day (60% of AL consumption) without micronutrient deficiency (NIA-31 fortified diet). The mice were maintained in a specific
CR reduces amyloid plaque number and size
We tested whether CR would attenuate AD-like amyloid accumulation in two established AD-transgenic mouse models: APPswe/ind [22] and APPswe + PS1M146L (APP + PS1)[15]. Both lines display an early onset of plaque deposition, with all the mice showing at least some Aβ-deposition by the young age of 21 and 25 weeks, respectively (Fig. 1(a) and (b)). The Aβ deposits of this sample were consistent with previous reports for these transgenic mice of these ages fed AL [11], [22].
In the APP + PS1 mice, the Aβ
Discussion
Short-term CR in early adulthood attenuated Aβ-plaque deposits in two transgenic mouse models of AD with early onset amyloid deposits. We detected Aβ-plaques in all the transgenic mice by age of 21–25 weeks, as expected [15], [22], and observed lower frequency in all CR groups. In the APPswe/ind mice, CR for only 6 weeks decreased the number of plaques and plaque-size by 40%; in the APP + PS1, 15 weeks of CR attenuated the Aβ load by 55%. Since CR reduces plaques in these two different familial
Acknowledgment
Supported by grants to C.E.F and T.E.M: AG13499 and Alzheimer Association Temple Award; D.M. and M.G.: AG 15490 and AG 18478; N.V.P: AG05901.
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- 1
Present address: Department of Gene Expression and Drug Discovery, City of Hope National Cancer Center, Duarte, CA 91010, USA.
- 2
T.E.M. and C.E.F. contributed equally to this work.