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Publication Detail
PICALM rescues glutamatergic neurotransmission, behavioural function, and survival in a Drosophila model of Aβ42 toxicity.
Alzheimer's disease (AD) is the most common form of dementia and the most prevalent neurodegenerative disease. Genome Wide Association Studies have linked PICALM to AD risk. PICALM has been implicated in Aβ42 production and turn-over, but whether it plays a direct role in modulating Aβ42 toxicity remains unclear. We found that increased expression of the Drosophila PICALM orthologue lap could rescue Aβ42 toxicity in an adult-onset model of AD, without affecting Aβ42 level. Imbalances in the glutamatergic system, leading to excessive, toxic stimulation have been associated with AD. We found that Aβ42 caused accumulation of pre-synaptic vesicular glutamate transporter (VGlut) and increased spontaneous glutamate release. Increased lap expression reversed these phenotypes back to control levels, suggesting that lap may modulate glutamatergic transmission. We also found that lap modulated the localisation of Amph, the homologue of another AD risk factor BIN1, and that Amph itself modulated post-synaptic glutamate receptor (GluRII) localisation. We propose a model where PICALM modulates glutamatergic transmission, together with BIN1, to ameliorate synaptic dysfunction and disease progression.
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