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

Abstract

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...

Prostaglandin I 2 upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

“…Each group contains 3 mice. The brains of animals in different groups were collected after anesthesia and perfusion as previously described (Yu et al ., 2015). …”

“…Cerebral spinal fluid (CSF) was collected according to a published method (Liu et al ., 2004) with minor modifications as previously described (Wang et al ., 2015; Yu et al ., 2015). …”

“…into WT or APP/PS1 transgenic mice as previously described (Yu et al ., 2015). Each group contains eight mice.…”

“…with the CSF of APP/PS1 mice. At indicated time intervals, the brains were harvested under anesthesia and perfusion as previously described (Yu et al ., 2015). …”

“…The tissue sections were immediately cultured in DMEM/high‐glucose medium with 10% FBS. In a separate set of experiments, the tissues were grown in serum‐free medium for an additional 24 h before incubation with PGI 2 (10 μ m ) or Aβ oligomers (1 μ m ) in the absence or presence of NS398 (10 μ m ), as previously described (Yu et al ., 2015). The tissue sections were fixed and immunostained with APH‐1 antibody by IHC staining kit (Invitrogen, Carlsbad, CA, USA).…”