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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 Aβ 42  production and turnover, but whether it plays a direct role in modulating Aβ 42  toxicity remains unclear. We found that increased expression of the  Drosophila PICALM  orthologue lap could rescue Aβ 42  toxicity in an adult-onset model of AD, without affecting Aβ 42  level. Imbalances in the glutamatergic system, leading to excessive, toxic stimulation, have been associated with AD. We found that Aβ 42  caused the accumulation of presynaptic 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 localization of amphiphysin (Amph), the homologue of another AD risk factor BIN1, and that Amph itself modulated postsynaptic glutamate receptor (GluRII) localization. We propose a model where PICALM modulates glutamatergic transmission, together with BIN1, to ameliorate synaptic dysfunction and disease progression.

PICALM rescues glutamatergic neurotransmission, behavioural function and survival in a Drosophila model of Aβ42 toxicity