How longevity research can lead to therapies for Alzheimer's disease: The rapamycin story

Abstract

The discovery that rapamycin increases lifespan in mice and restores/delays many aging phenotypes has led to the speculation that rapamycin has 'anti-aging' properties. The major question discussed in this review is whether a manipulation that has anti-aging properties can alter the onset and/or progression of Alzheimer's disease, a disease in which age is the major risk factor. Rapamycin has been shown to prevent (and possibly restore in some cases) the deficit in memory observed in the mouse model of Alzheimer's disease (AD-Tg) as well as reduce Aβ and tau aggregation, restore cerebral blood flow and vascularization, and reduce microglia activation. All of these parameters are widely recognized as symptoms central to the development of AD. Furthermore, rapamycin has also been shown to improve memory and reduce anxiety and depression in several other mouse models that show cognitive deficits as well as in 'normal' mice. The current research shows the feasibility of using pharmacological agents that increase lifespan, such as those identified by the National Institute on Aging Intervention Testing Program, to treat Alzheimer's disease.

Keywords: Alzheimer's disease; Behavior; Cognition; Rapamycin.

Fig. 1.

Effect of Rapamycin on the Memory of AD-Tg Mice assessed by the Morris Water Maze. Graph A: data taken from Caccamo et al. (2010) for 3XTg-AD (AD-Tg) and non-transgenic (Control) mice fed rapamycin (black bars) or a control diet (white bars) starting at 6 months of age for 10 weeks. Graph B: data were taken from Spilman et al. (2010) for hAPP(J20) (AD-Tg) and non-transgenic (Control) mice fed rapamycin (black bars) or a control (white bars) diet starting at 4 months of age for 13 weeks.

Fig. 2.

Effect of Rapamycin on plaques and tangles in brains of 3XTg-AD mice. The levels of Aβ₄₂ in whole brain (A,B) or hippocampus (C,D), fibrillar aggregates of Aβ (E, F), tau pathology as measured by hyperphosphorylation at Ser212 and Thr214 (G, H), and microglia activation (I, J) were measured in 2-month-old mice fed rapamycin or a control diet for 16 months (data taken from Majumder et al. (2011).

Fig. 3.

Effect of rapamycin on CBF, vascularization, and cerebral amyloid angiopathy in hAPP(J20) mice. Panels A and B show CBF in various brain regions with brighter colors indicating increased blood flow. Panels C and D show magnetic resonance angiography images of brains showing vasculature with the arrows pointing to regions of the brain where rapamycin restored vascular density. Panels E and F show Aβ (shown in red) associated with brain blood vessels (shown in green). The data were taken from Lin et al. ( 2013) for 7-month-old mice fed rapamycin or a control diet for 16 weeks.

Fig. 4.

Diagram showing the protective effect of rapamycin in AD using the ‘two-hit’ process described by Zlokovic (2011). Rapamycin prevents the first hit’ by increasing the clearance of Aβ through the restoration of vascular integrity. Rapamycin also blocks the second ‘hit’ by inducing autophagy preventing the accumulation of Aβ in the brain counteracting the hyperactivation of mTOR, which occurs in the brains of AD-Tg mice and patients.

Fig. 5.

Effect of rapamycin of memory on ‘normal’ laboratory mice. Mice were fed rapamycin (black bars) or a control diet (white bars) for various lengths of time and cognitive performance measured by the Morris water Maze. The right graph is 2-month-old mice fed rapamycin for 16 months (data taken from Majumder et al. 2012). The middle graph is 4-month-old mice fed rapamycin for 16 weeks (data taken from Halloran et al., ( 2012). The right graph is 4-month-old mice fed rapamycin for 11 months (data taken from Neff et al. 2013).

Fig. 6.

Diagram showing pathways reported to change with rapamycin treatment that could impact the changes observed in behavior and cognition observed in laboratory rodents.