PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

Abstract

Multiple intracellular signals are altered in Alzheimer's disease brain tissues, including the PI3K/Akt pathway. However, the pathological relevance of such alterations is poorly understood. In vitro studies yield results that seem to be consistent with the conventional perception in which an up-regulation of the cell survival pathway, PI3K pathway, is protective in Alzheimer's disease pathogenesis. The current in vivo genetic approach, however, reveals that inhibition of the PI3K pathway leads to rescuing of the β-amyloid peptide (Aβ)-induced memory loss in the Drosophila brain. We began our inquiry into the molecular basis of this memory loss by studying Aβ42-induced enhancement of long-term depression. We found that long-term depression is restored to a normal level through inhibition of PI3K activity. Aβ42-induced PI3K hyperactivity is directly confirmed by immunostaining of the PI3K phosphorylation targets, phospholipids. Such observations lead to the following demonstration that Aβ42-induced memory loss can be rescued through genetic silencing or pharmacological inhibition of PI3K functions. Our data suggest that Aβ42 stimulates PI3K, which in turn causes memory loss in association with an increase in accumulation of Aβ42 aggregates.

Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss

“…These observations lead us to hypothesize that EGFR hyperactivity-dependent memory loss is due to acute effects of Aβ oligomers. It is known that Aβ oligomers are capable of disrupting long-term synaptic plasticity (1) and the downstream signaling pathways of EGFR, such as PI3-kinase and Ras, which are important in regulating long-term synaptic plasticity (17,37,43).…”

“…In Drosophila, expression of a secretory form of human Aβ42 in the brain recapitulates AD-like features, such as age-dependent accumulation of Aβ deposits, memory loss, and late-onset severe neurodegeneration (20,21). Our earlier work reveals a role of PI3-kinase in Aβ42-induced alteration in long-term depression and memory loss (17). To find receptors associated with this PI3-kinase effect, we first evaluated behavioral effects of overloaded insulin receptor (InR) or EGFR in Aβ42-expressing Drosophila brains.…”

“…For the purpose of seeing a stronger memory-loss phenotype, we selected 3-d-old male adults (elav-Gal4/Y;UAS-Aβ42/+) for drug treatment. Memory scores were measured at day 10 of posteclosion following 4 h of drug feeding each day for 7 consecutive days (17) (Fig. 1C and Fig.…”

“…First, following the direction of a synaptic-plasticity-based, mechanism-guided study, we continued to work on the signal transduction pathway of PI3-kinase that has been shown to mediate an Aβ-induced change in long-term synaptic depression as well as the Aβ-induced memory loss in Aβ42-expressing Drosophila, which recapitulates several ADlike symptoms (17). These efforts led us to find Aβ42 oligomersinduced activation of the epidermal growth factor receptor (EGFR) and the rescue of Aβ-induced memory loss in transgenic Drosophila and APP/PS1 double transgenic mouse models through treatments with clinically available EGFR inhibitors.…”

<em>Drosophila</em> Adult Olfactory Shock Learning

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AbstractDrosophila have been used in classical conditioning experiments for over 40 years, thus greatly facilitating our understanding of memory, including the elucidation of the molecular mechanisms involved in cognitive diseases [1][2][3][4][5][6][7]

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