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[Kadaicher1]

PBT2 rapidly prevents normal age related cognitive decline.
New research from Florey institute's Prof Adlard.
Full Text
http://onlinelibrary.wiley.com/doi/10.1111/acel.12178/pdf

This differs from normal preclinical studies because there are prodromal patients in a PBT2 clinical trial about to finish this year. Not quite the normal 10 year wait.


Accepted Date : 21-Oct-2013
Article type : Original Paper

A Novel Approach To Rapidly Prevent Age-Related Cognitive Decline

Running title: PBT2 prevents cognitive decline

Paul A. Adlard*,#,a, Amelia Sedjahteraa
, Lydia Gunawana
, Lisa Braya
, Dominic Hareb
, Jessica
Learb
, Philip Dobleb
, Ashley I. Busha
, David I. Finkelsteina
, Robert A. Cherny*,a.





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Summary
The loss of cognitive function is a pervasive and often debilitating feature of the ageing process for which there are no effective therapeutics. We hypothesized that a novel metal
chaperone (PBT2, Prana Biotechnology) 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 elevated levels of specific glutamate receptors

PBT2 increases dendritic spine density
In order to provide insight into the potential mechanisms of action of PBT2 we examined several physiological parameters related to learning and memory/cognition that we have previously shown to be altered following PBT2 treatment in transgenic mouse models of AD.
A number of these “biomarkers” may be relevant to both normal and pathological aging, as well as to other diseases or conditions that are not necessarily age-dependent.

Using Golgi impregnation, we examined the effect of PBT2 on dendritic spine density and dendritic length in the hippocampus. Dendritic spines are dynamic anatomical structures believed critical for learning and memory, which are rapidly modulated in response to various stimuli, and that are the site of the majority of post-synaptic excitatory glutamatergic synapses in the hippocampus. The molecular constituents of spines, and the associated dendritic length/ branching to a lesser extent, may promote functional plasticity and/or be modulated in both normal and pathological aging. While PBT2 did not result in a statistically significant change in dendritic length (Basal: PBT2 (+14%), p>0.05; Apical: PBT2 (+5%), p>0.5), there was a significant increase in spine density on the basal and apical dendrites (Basal: PBT2 (+15%), P=0.02; Apical: PBT2 (+14%), P=0.009) (Fig. 2a, 2b). Such anatomical alterations (elevated spine density in the absence of any change in dendritic length) have also been observed following stimuli, such as environmental enrichment, which also enhances spatial memory (Moser et al.1997). Thus, PBT2 may be modulating the activity/plasticity of glutamatergic synapses to effect the improved learning and memory
observed in the aged mice. Mechanistically, this may relate to an effect on long-term potentiation, whose induction and maintenance is impaired in the aged hippocampus (Barnes 1979; Barnes et al. 2000), and whose magnitude is greatest in basal dendrites.

PBT2 increases markers of neurogenesis and neuron number While the loss of synaptic connectivity in the context of normal aging is generally considered to be a mediator of cognitive decline, as opposed to overt neuron loss, we assessed markers of both neurogenesis and neuron number in the hippocampus, as this may contribute to the function of this brain region, as well as limit subsequent susceptibility to degeneration resulting from the onset of neurological disease. A histological examination of surrogate
markers for neurogenesis revealed that PBT2 significantly increased the number of Ki-67 positive cells (PBT2 (+67%), P=0.05), a proliferation marker, and doublecortin positive cells
(PBT2 (+130%), P=0.01), a marker for immature neurons, in the hippocampus (Fig. 2c, Fig. 2e). Ki67 positive cells were also significantly elevated (PBT2 (+214%), P=0.008) surrounding the dorsal third ventricle following PBT2 treatment (n=5-7/group, 4
sections/group; data not shown).