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.