Elevation of Brain Magnesium Prevents and Reverses Cognitive Deficits and Synaptic Loss in Alzheimer's Disease Mouse Model

Li, Wei; Jia, Yu; Liu, Yong; Huang, Xiaojie; Abumaria, Nashat; Zhu, Ying; Huang, Xiji; Xiong, Wenxiang; Ren, Chi; Liu, Xian-Guo; Chui, Dehua; Liu, Guosong

doi:10.1523/jneurosci.4610-12.2013

Cited by 65 publications

(70 citation statements)

References 8 publications

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“…MgT treatment improved the cognitive decline of the APP/PS1 mice after 5 mo of administration. In agreement with our observations, Li et al (2) found that MgT attenuates cognitive decline in APP/PS1 mice. Similar observations have been reported in rats and humans (39,40).…”

supporting

confidence: 94%

By suppressing the expression of anterior pharynx‐defective‐1α and ‐1β and inhibiting the aggregation of β‐amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice

Guan

Guo

et al. 2015

FASEB j.

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Alzheimer's disease (AD) is associated with a magnesium ion (Mg 2+ ) deficit in the serum or brain. However, the mechanisms regulating the roles of Mg 2+ in the pathologic condition of AD remain unknown. We studied whether brain Mg 2+ can decrease b-amyloid (Ab) deposition and ameliorate the cognitive decline in a model of AD, the APPswe/PS1DE9 transgenic (Tg) mouse. We used a recently developed compound, magnesium-L-threonate (MgT), for a treatment that resulted in enhanced clearance of Ab in an anterior pharynx-defective (APH)-1a/-1b-dependent manner. To further explore how MgT treatment inhibits cognitive decline in APP/PS1 Tg mice, the critical molecules for amyloid precursor protein (APP) cleavage and signaling pathways were investigated. In neurons, ERK1/2 and PPARg signaling pathways were activated by MgT treatment, which in turn suppressed (by >80%) the expression of APH-1a/-1b, which is responsible for the deposition of Ab and potentially contributes to the memory deficit that occurs in AD. More important, Ab oligomers in the cerebrospinal fluid (CSF) further promoted the expression of APH-1a/-1b (by >2.5-fold), which enhances the g-cleavage of APP and Ab deposition during AD progression. These findings provide new insights into the mechanisms of AD progression and are instrumental for developing better strategies to combat the disease.-Yu, X., Guan, P.-P., Guo, J.-W., Wang, Y., Cao, L.-L., Xu, G.-B., Konstantopoulos, K., Wang, Z.-Y., Wang, P. By suppressing the expression of anterior pharynxdefective-1a and -1b and inhibiting the aggregation of b-amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice. FASEB J. 29, 5044-5058 (2015). www.fasebj.orgAlzheimer's disease (AD) is usually characterized by cognitive decline and dementia in aged people. Clinically, it is diagnosed by the accumulation of b-amyloid (Ab) protein in amyloid plaques (APs) and the hyperphosphorylation of tau in neurofibrillary tangles (NFTs) (1). Although the mechanisms of Ab deposition and tau phosphorylation have not been thoroughly delineated, recent reports have revealed that Mg 2+ elevation may be involved in Ab clearance (2). These observations are based on prior studies that suggested that brain magnesium ion (Mg 2+ ) levels (3) and serum Mg 2+ concentration (4) are significantly lower in patients with AD than in age-matched normal subjects. In light of these studies, dyshomeostasis of Mg 2+ in the brain may be involved in the pathogenesis and progression of AD.Although the mechanisms that regulate Mg 2+ concentrations over the course of the development of AD have yet to be defined, the potential roles of Mg 2+ in AD have been examined in a few investigations. For example, it has been shown that a reduced level of Mg 2+ blocks the NMDA receptor (NMDAR)-mediated Ca 2+ influx that is essential for associative learning and long-term memory formation in Drosophila (5). The administration of magnesium-L-threonate (MgT) to aged rats increases Mg 2+ levels in the...

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supporting

confidence: 94%

By suppressing the expression of anterior pharynx‐defective‐1α and ‐1β and inhibiting the aggregation of β‐amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice

Guan

Guo

et al. 2015

FASEB j.

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“…Our data are consistent with a growing animal literature suggesting that chronic MgT treatment may have clinical relevance since it has been shown to reduce learned helplessness (a model of human depression; Abumaria et al, 2009), enhance the efficacy of fear extinction (Abumaria et al, 2011), and reduce cognitive deficits in a mouse model of Alzheimer’s Disease (Liu et al, 2009). Here we demonstrated that MgT increased the rate of CTA extinction, reduced SR of a CTA, and interacted with EU extinction procedures to further reduce SR of a CTA.…”

Section: Discussionsupporting

confidence: 90%

Chronic dietary magnesium-L-threonate speeds extinction and reduces spontaneous recovery of a conditioned taste aversion

Mickley

Hoxha

Luchsinger

et al. 2013

Pharmacology Biochemistry and Behavior

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Elevation of brain magnesium enhances synaptic plasticity and extinction of conditioned fear memories. This experiment examined the generalizability of this phenomenon by studying the effects of a novel magnesium compound, magnesium-L-threonate (MgT), on conditioned taste aversion (CTA) extinction and spontaneous recovery (SR). Adult male Sprague-Dawley rats were maintained on a 23-hour water deprivation cycle and acquired a CTA following the taste of a CS [0.3% saccharin + 16mg/ml MgT (SAC+MgT)] paired with a US [81 mg/kg (i.p.) Lithium Chloride (LiCl)]. Following CTA acquisition, rats drank a water + MgT solution for up to 1 hour/day over the next 31 days. For 14 additional days, some animals continued water + MgT treatment, but others drank water only to allow MgT to be eliminated from the body. We then employed 2 different extinction paradigms: (1) CS-Only (CSO), in which SAC was presented, every-other day, or (2) Explicitly Unpaired (EU), in which both SAC and LiCl were presented, but on alternate days. EU extinction procedures have been shown to speed CTA extinction and reduce spontaneous recovery of the aversion. Throughout extinction, half of the rats in each group continued to drink MgT (now in SAC or supplemental water+MgT solution), whereas the other half drank SAC only/water only until SAC drinking reached ≥ 90% of baseline (asymptotic extinction). Rats receiving MgT just before/during extinction drank less SAC on the first day of extinction suggesting that they had retained a stronger CTA. MgT enhanced the rate of extinction. Furthermore, the MgT-treated rats showed a relatively modest SR of the CTA 30 days later – indicating that the extinction procedure was more effective for these animals. Our data suggest that long-term dietary MgT may enhance the consolidation/retention of a CTA, speed extinction, and inhibit SR of this learned aversion.

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“…Selective exploration of the novel object is taken as evidence that the preexposed object is recognised as familiar. This widely-used task has revealed deficits in a wide range of different 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 transgenic models of AD [32], and impairments are routinely observed in older APPswe/PS1dE9 mice [33,34,35,36,37; but see 38]. SOR deficits are also occasionally reported in these mice at 6-7 months of age [34,39,40,41], but never in animals younger than 6 months [40,42].…”

Section: Introductionmentioning

confidence: 99%

Deficits in object-in-place but not relative recency performance in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: Implications for object recognition

Bonardi

Pardon

Armstrong

2016

Behavioural Brain Research

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Performance was examined on three variants of the spontaneous object recognition (SOR) task, in 5-month old APPswe/PS1dE9 mice and wild-type littermate controls. A deficit was observed in an object-in-place (OIP) task, in which mice are preexposed to four different objects in specific locations, and then at test two of the objects swap locations (Experiment 2). Typically more exploration is seen of the objects which have switched location, which is taken as evidence of a retrieval-generated priming mechanism. However, no significant transgenic deficit was found in a relative recency (RR) task (Experiment 1), in which mice are exposed to two different objects in two separate sample phases, and then tested with both objects. Typically more exploration of the firstpresented object is observed, which is taken as evidence of a self-generated priming mechanism. Nor was there any impairment in the simplest variant, the spontaneous object recognition (SOR) task, in which mice are preexposed to one object and then tested with the familiar and a novel object. This was true regardless of whether the sample-test interval was 5 minutes (Experiment 1) or 24 hours (Experiments 1 and 2). It is argued that SOR performance depends on retrieval-generated priming as well as self-generated priming, and our preliminary evidence suggests that the retrieval-generated priming process is especially impaired in these young transgenic animals . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 The aim of our research has been to identify early cognitive signs of AD in one specific genetic model, the double-transgenic APPswe/PS1dE9 mouse. This may be the best-characterised transgenic model of AD to date, co-expressing the mutated Swedish APP gene and also the exon-9 deleted variant of the PS1 gene [5]. Elevated levels of oligomeric Aβ in the cortex and hippocampus have been observed at 3.5 months of age in these mice; these changes are accompanied by synaptic deficits [6,7], and are also closely associated with swollen dystrophic cholinergic neurites [8].Although the amyloid plaques characteristic of AD have been reported at 4 months of age in these mice, it is only from 6 months that they are consistently observed [9]. Aβ deposition is paralleled by progressive degeneration of monaminergic [10,11] and striatal [12] neurons, and neuroinflammatory reactions [13] which mirror human AD pathology. These animals also recapitulate the age-related cognitive decline characteristic of AD [14], which is thought to depend on these neuropathological changes.The neuropathology that develops in AD in general, and in this mouse model in particular, is well specified. But precisely which aspects of this brain pathology underlie the cognitive deficits that are such a central feature of AD is still under debate [15]. In this particular mouse line, some...

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Elevation of Brain Magnesium Prevents and Reverses Cognitive Deficits and Synaptic Loss in Alzheimer's Disease Mouse Model

Cited by 65 publications

References 8 publications

By suppressing the expression of anterior pharynx‐defective‐1α and ‐1β and inhibiting the aggregation of β‐amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice

By suppressing the expression of anterior pharynx‐defective‐1α and ‐1β and inhibiting the aggregation of β‐amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice

Chronic dietary magnesium-L-threonate speeds extinction and reduces spontaneous recovery of a conditioned taste aversion

Deficits in object-in-place but not relative recency performance in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: Implications for object recognition

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