Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

TorreyPines Therapeutics, Inc., La Jolla, CA 92037, USA.
Neuron (Impact Factor: 15.05). 09/2010; 67(5):769-80. DOI: 10.1016/j.neuron.2010.08.018
Source: PubMed


Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Abeta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Abeta(40) levels while concomitantly elevating levels of Abeta(38) and Abeta(37). Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Abeta(42); chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs).

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Available from: Kenneth Stauderman
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    • "Alzheimer's disease (AD), with the clinical symptoms cognitive declining, irreversible memory losing, disorientation, language impairment, etc, threatened millions of elderly people [1] [2]. It has been well established that the cytotoxic beta-amyloid (Aβ) was a trigger of the pathological cascade of events leading to AD [3] [4] [5] [6]. "

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    • "However, we cannot rule out the possibility that the γ-secretase is involved in Aβ metabolism in (−)epicathechin treated mice, γ-secretase is a large multimeric membrane-bound protein composed of presenilins (PS1), nicastrin, and Aph-1. Mutations in three different genes, APP and presenilin-1 and -2 (PS1 and PS2), are known to cause early onset familial AD (27, 28). For this reason, γ-secretase has been considered as a plausible molecular target as a means to interfere with the production of Aβ. "
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    ABSTRACT: Background: Alzheimer’s disease (AD) is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The clearance of Aβ from the brain and anti-inflammation are potential important strategies to prevent and treat disease. In a previous study, we demonstrated the grape seed extract (GSE) could reduce brain Aβ burden and microglia activation, but which polyphenol plays a major role in these events is not known. Here, we tested pharmacological effects of (−)epicatechin, one principle polyphenol compound in GSE, on transgenic AD mice. Methods: APP/PS1 transgenic mice were fed with (−)epicatechin diet (40 mg/kg/day) and curcumin diet (47 mg/kg/day) at 3 months of age for 9 months, the function of liver, Aβ levels in the brain and serum, AD-type neuropathology, plasma levels of inflammatory cytokines were measured. Results: Toward the end of the experiment, we found long-term feeding of (−)epicatechin diet was well tolerated without fatality, changes in food consumption, body weight, or liver function. (−)Epicatechin significantly reduced total Aβ in brain and serum by 39 and 40%, respectively, compared with control diet. Microgliosis and astrocytosis in the brain of Alzheimer’s mice were also reduced by 38 and 35%, respectively. The (−)epicatechin diet did not alter learning and memory behaviors in AD mice. Conclusion: This study has provided evidence on the beneficial role of (−)epicatechin in ameliorating amyloid-induced AD-like pathology in AD mice, but the impact of (−)epicatechin on tau pathology is not clear, also the mechanism needs further research.
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    • "The major components of senile plaques are amyloid beta (Aβ) (1,5,6). Most of all, Aβ accumulation and senile plaques played an important role in the development of the AD (7-9). Aβ are derived by cleavage of amyloid precursor protein (APP). "
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    ABSTRACT: Extracellular accumulation of amyloid beta protein (Aβ) plays a central role in Alzheimer's disease (AD). Some metals, such as copper, lead, and aluminum can affect the Aβ accumulation in the brain. However, the effect of mercury on Aβ accumulation in the brain is not clear. Thus, this study was proposed to estimate whether mercury concentration affects Aβ accumulation in PC12 cells. We treated 10, 100, and 1000 nM HgCl2 (Hg) or CH3HgCl2 (MeHg) for 48 hr in PC12 cells. After treatment, Aβ40 in culture medium increased in a dose- and time-dependent manner. Hg and MeHg increased amyloid precursor protein (APP), which is related to Aβ production. Neprilysin (NEP) levels in PC12 cells were decreased by Hg and MeHg treatment. These results suggested that Hg induced Aβ accumulation through APP overproduction and reduction of NEP.
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