Authors Name: 
Sadaf Sohrabi
University: 
University of Edinburgh
Category: 
Life Sciences
Award winner

Are Amyloid-Beta Mediated Degenerative Changes Dependent Upon Tau In A Novel Mouse Model Of Alzheimer's Disease?

Alzheimer’s disease (AD) is a devastating neurodegenerative condition affecting 46 million people worldwide. Two pathological proteins, amyloid-beta (Aβ) and tau, are heavily implicated in AD progression, however their exact roles remain elusive.
Here the pathological features of a new AD mouse model are characterised for the first time. The mice express human amyloid mutations (hAPP/PS1) alongside tetracycline-regulatable wildtype human tau (hTau), but they lack endogenous mouse tau known to worsen the phenotypes of human APP and tau expressing mice. Four genotypes were studied: control, hTau, hAPP/PS1, and hAPP/PS1+hTau, allowing the precise interactions between the two proteins to be investigated. Critically, the bulk of AD research thus far has focused on the pathogenic roles of amyloid, so this new model will provide invaluable insight into the relatively ambiguous functions of tau.
Previous behavioural testing using an established novel object recognition task detected memory deficits in tau-expressing mice at nine months. This work aimed to investigate the pathology of the mice at nine months, to identify any alterations which may underlie their memory deficits. 
Cerebral volumes were measured by stereology. Aβ plaque burden, oligomeric Aβ (oAβ) halo area/diameter, and tau phosphorylation were assessed by immunohistochemistry. Synaptic Aβ42 levels were quantified by an Aβ42-specific ELISA.
No significant differences were noted in cerebral volumes, oAβ halo area/diameter, or synaptic Aβ42 levels between all four genotypes (p>0.05). Hyperhophosphorylated tau surrounding Aβ plaques was evident in hAPP/PS1+hTau mice, with these mice demonstrating significantly fewer cortical (p=0.0184) and hippocampal (p=0.0335) plaques than hAPP/PS1 mice.
The previously observed memory deficits are unlikely to arise due to cerebral volume, oAβ halo area/diameter, or synaptic Aβ42 alterations. However, plaque burdens changes and tau hyperphosphorylation may underpin deficits. The results of this work highlight a central role of tau protein, thus further investigations into tau may reveal much-needed therapeutic targets.