Metal Ionophore Treatment Restores Dendritic Spine Density and Synaptic Protein Levels in a Mouse Model of Alzheimer's Disease

Abstract

We have previously demonstrated that brief treatment of APP transgenic mice with metal ionophores (PBT2, Prana Biotechnology) rapidly and markedly improves learning and memory. To understand the potential mechanisms of action underlying this phenomenon we examined hippocampal dendritic spine density, and the levels of key proteins involved in learning and memory, in young (4 months) and old (14 months) female Tg2576 mice following brief (11 days) oral treatment with PBT2 (30 mg/kg/d). Transgenic mice exhibited deficits in spine density compared to littermate controls that were significantly rescued by PBT2 treatment in both the young (+17%, p<0.001) and old (+32%, p<0.001) animals. There was no effect of PBT2 on spine density in the control animals. In the transgenic animals, PBT2 treatment also resulted in significant increases in brain levels of CamKII (+57%, p = 0.005), spinophilin (+37%, p = 0.04), NMDAR1A (+126%, p = 0.02), NMDAR2A (+70%, p = 0.05), pro-BDNF (+19%, p = 0.02) and BDNF (+19%, p = 0.04). While PBT2-treatment did not significantly alter neurite-length in vivo, it did increase neurite outgrowth (+200%, p = 0.006) in cultured cells, and this was abolished by co-incubation with the transition metal chelator, diamsar. These data suggest that PBT2 may affect multiple aspects of snaptic health/efficacy. In Alzheimer's disease therefore, PBT2 may restore the uptake of physiological metal ions trapped within extracellular β-amyloid aggregates that then induce biochemical and anatomical changes to improve cognitive function.

Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease

“…Deferoxamine (DFO), the natural prototype iron chelator/radical scavenger slowed the clinical progression of AD dementia (Crapper et al 1991) and inhibited amyloidogenic processing of amyloid precursor protein (APP) and reversed iron-induced memory deficits and tau phosphorylation in mice model of AD (Guo et al 2013a,b). Clioquinol and PBT2, 8-hydroxyquinoline bidentate ligands, attenuated cognitive loss and inhibited Aβ accumulation in AD transgenic mice (Cherny et al 2001;Adlard et al 2011). …”

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

“…In mouse model studies, metal ion chelator clioquinol (iodochlorhydroxyquin) [252] and DP-109 (1,2-bis(2-aminophenyloxy)ethane-N,N,N 0 ,N 0 -bis(2-octadecyloxyethyl)ester, N,N 0 -disodium salt) can reduce Ab toxicity and levels of insoluble Ab aggregation as well as plaque formation [169,171]. In addition, an improved analog of clioquinol, PBT2, shows more effective rescue of AD symptoms in mouse models [253][254][255]. Although PBT2 and CQ acting as ionophores or metal chaperones are also proposed [256], the data strongly indicate that reuse and redistribution of metal ions are critical to AD progression.…”

Role of APP for dendritic spine formation and stability

“…D'Amelio et al 2011), 4-monthold(Lanz et al 2003;Adlard et al 2011) and 14-month-old(Adlard et al 2011) Tg2576 mice. A recent Golgi study on CA1 pyramidal neurons of 5.5-month-old female Tg2576 revealed a decrease in spine density only at basal proximal dendrites but not at proximal or distal apical dendrites(Perez-Cruz et al 2011).…”