A novel approach to rapidly prevent age‐related cognitive decline

Abstract

The loss of cognitive function is a pervasive and often debilitating feature of the aging process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2; Prana Biotechnology, Parkville, Victoria, Australia) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis. There were also increased levels of specific glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-d-aspartate), the glutamate transporter (VGLUT1) and glutamate itself. Markers of synaptic plasticity [calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, CREB, synaptophysin] were also increased following PBT2 treatment. We also demonstrate that PBT2 treatment results in a subregion-specific increase in hippocampal zinc, which is increasingly recognized as a potent neuromodulator. These data demonstrate that metal chaperones are a novel approach to the treatment of age-related cognitive decline.

Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: Maintenance of brain iron homeostasis

“…PBT2 improved cognition in aged C57Bl/6 mice [82] and APP transgenic Tg2576 mice, effects associated with decreased interstitial Aβ [83]. A Phase II trial with PBT2 in 78 AD patients showed a reduction in CSF Aβ levels of CSF and enhanced performance metrics.…”

Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse

“…It was rediscovered in 2000s to be a drug candidate for Alzheimer's disease since treatment with CQ rapidly reduced plaques in Tg2576 transgenic mice (Cherny et al, 2001). It was later found that CQ also showed beneficial effects in cellular and animal models of PD (Lei et al, 2012;Kaur et al, 2003Kaur et al, , 2009Tardiff et al, 2012), Huntington's disease (HD) (Nguyen et al, 2005), cancer (Chen et al, 2007;Ding et al, 2008;Yu et al, 2009), and it can protect against aging sequelae (Wang et al, 2009;Adlard et al, 2014a). It also was tested in a Phase 2 clinical trial in AD, which reported that it was well tolerated and that treatment slowed cognitive deterioration (Ritchie et al, 2003).…”

Zinc Transporter-3 Knockout Mice Demonstrate Age-Dependent Alterations in the Metalloproteome

“…In the last few decades the role of metals in pathological ageing has also gained increasing attention, with strong preclinical evidence for their role in the onset and progression of numerous neurodegenerative diseases such as Huntington's disease, schizophrenia, Parkinson's disease and Alzheimer's disease [18]. More recently, utilising the ZnT3 KO mouse line and other methods, we and others have also demonstrated a key role for zinc in "normal" synaptic plasticity and learning/memory via interactions on key neuronal signalling cascades and proteins [7][8][9][19][20][21][22]. Ultimately, the role of zinc in higher order cognitive function may well intersect with its effect on these and other age-and disease-related pathways.…”

“…Approximately 10%-15% of brain zinc exists as chelatable zinc primarily within synaptic vesicles at glutamatergic synapses, highlighting its importance in synaptic plasticity/cognition. Our discoveries highlighted the critical importance of this pool of zinc, and the synaptic zinc transporter (ZnT3 (SLC30A3)), in cognition [6][7][8][9]. Specifically, we reported that there were age-dependent deficits in learning and memory in the ZnT3 knockout (KO) mice that were manifest at 6 months of age (but not at 3 months), and which were associated with significant deficits in a suite of key hippocampal proteins involved in learning and memory.…”