As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.

Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn 2ϩ levels, which is predicted to regulate normal cognitive function. Surprisingly, previous studies found that 6-to 10-week-old ZnT3 knock-out (KO) mice did not show impairment in the Morris water maze. We hypothesized that older ZnT3 KO animals would display a cognitive phenotype. Here, we report that ZnT3 KO mice exhibit age-dependent deficits in learning and memory that are manifest at 6 months but not at 3 months of age. These deficits are associated with significant alterations in key hippocampal proteins involved in learning and memory, as assessed by Western blot. These include decreased levels of the presynaptic protein SNAP25 (Ϫ46%; p Ͻ 0.01); the postsynaptic protein PSD95 (Ϫ37%; p Ͻ 0.01); the glutamate receptors AMPAR (Ϫ34%; p Ͻ 0.01), NMDAR2a (Ϫ64%; p Ͻ 0.001), and NMDAR2b (Ϫ49%; p Ͻ 0.05); the surrogate marker of neurogenesis doublecortin (Ϫ31%; p Ͻ 0.001); and elements of the BDNF pathway, pro-BDNF (Ϫ30%; p Ͻ 0.05) and TrkB (Ϫ22%; p Ͻ 0.01). In addition, there is a concomitant decrease in neuronal spine density (Ϫ6%; p Ͻ 0.05). We also found that cortical ZnT3 levels fall with age in wild-type mice (Ϫ50%; p Ͻ 0.01) in healthy older humans (ages, 48 -91 years; r 2 ϭ 0.47; p ϭ 0.00019) and particularly in Alzheimer's disease (AD) (Ϫ36%; p Ͻ 0.0001). Thus, age-dependent loss of transsynaptic Zn 2ϩ movement leads to cognitive loss, and since extracellular ␤-amyloid is aggregated by and traps this pool of Zn 2ϩ , the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.

Ceruloplasmin is an iron-export ferroxidase that is abundant in plasma and also expressed in glia. We found a ∼80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of idiopathic Parkinson disease (PD) cases, which could contribute to the pro-oxidant iron accumulation that characterizes the pathology. Consistent with a role for ceruloplasmin in PD etiopathogenesis, ceruloplasmin knockout mice developed parkinsonism that was rescued by iron chelation. Additionally, peripheral infusion of ceruloplasmin attenuated neurodegeneration and nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model for PD. These findings show, in principle, that intravenous ceruloplasmin may have therapeutic potential in PD.

Electrospinning has been employed extensively in tissue engineering to generate nanofibrous scaffolds from either natural or synthetic biodegradable polymers to simulate the cellular microenvironment. Electrospinning rapidly produces fibers of the nanolength scale and the process offers many opportunities to tailor the physical, chemical, and biological properties of a material for specific applications and cellular environments. There is growing evidence that nanofibers amplify certain biological responses such as contact guidance and differentiation, however this has not been fully exploited in tissue engineering. This review addresses the cellular interactions with electrospun scaffolds, with particular focus on neural, bone, cartilage, and vascular tissue regeneration. Some aspects of scaffold design, including architectural properties, surface functionalization and materials selection are also addressed.

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This study compares the basal ganglia of rats, marmosets, macaques, baboons, and humans. It uses established protocols to estimate the volume and number of neurons within the output nuclei (internal globus pallidus, IGP; and nondopaminergic substantia nigra, SNND), two internal relay and modulating nuclei (subthalamic nucleus, STh; and external globus pallidus, EGP), and a modulator of the striatum (dopaminergic substantia nigra, SND). Nuclear boundaries were defined by using immunohistochemistry for striatal afferents. Total numbers of Nissl-stained and parvalbumin-immunoreactive neurons were calculated by using the fractionator technique. Comparisons between species were standardized relative to brain mass (rats < marmosets < macaques < baboons < humans). The EGP consistently had more neurons relative to the IGP, STh, and SND, which had similar neuronal numbers within each species. The SNND had proportionally more neurons in rats than in primates (especially humans). The distribution of SND neurons varied substantially between rats and primates (very few ventrally located neurons in rats) with humans containing fewer SND neurons than other primates. The reduction in SND neurons in humans suggests less dopaminergic regulation of the basal ganglia system compared with other species. The consistency in the number of IGP neurons across all species, combined with the reduction in SNND neurons in humans, suggests a greater emphasis on output pathways through the IGP and that there are proportionally more STh and EGP neurons in humans.