Linking Aβ42-Induced Hyperexcitability to Neurodegeneration, Learning and Motor Deficits, and a Shorter Lifespan in an Alzheimer’s Model

Abstract

Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly. β-amyloid (Aβ) accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. Aβ has been shown to promote neuronal hyperactivity, which is consistent with enhanced seizure activity in mouse models and AD patients. Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of AD. Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. Interestingly, we find that loss of Kv4 alone results in learning and locomotion defects, as well as a shortened lifespan. To test whether the Aβ42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in Aβ42-expressing animals. We show that restoration of Kv4 attenuated age-dependent learning and locomotor deficits, slowed the onset of neurodegeneration, and partially rescued premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.

Cholinergic Homeostatic Synaptic Plasticity Drives the Progression of Aβ-Induced Changes in Neural Activity

“…In this report, we use a transgenic Drosophila line that overexpresses a secreted form of the human Ab42 peptide as a model to examine the effects of Ab42 on cholinergic synaptic function and to gain insight into the potential role of homeostatic mechanisms driving Ab-induced adaptive and maladaptive changes in cholinergic activity. These flies exhibit many of the pathogenic hallmarks associated with AD (Finelli et al, 2004;Iijima et al, 2004Iijima et al, , 2008Ping et al, 2015). We show that both Ab40 and Ab42 induce an early enhancement in spontaneous cholinergic synaptic events and that this increased activity is followed by a subsequent reduction in spontaneous events, a progression that parallels what has been suggested to occur in cholinergic regions of mammalian AD models.…”

“…These opposing changes are intriguing because mammalian Ab models have also been reported to exhibit both increases and decreases in spontaneous activity; however, little is known about how these opposing effects are induced and how they are related. Since previous studies using this transgenic line have shown that significant neuronal loss is not observed in Ab42-expressing brains until 25 days AE (Iijima et al, 2004;Ping et al, 2015), the decrease in synaptic activity seen at 9-13 days AE may be due to synaptic dysfunction that precedes neuronal death. Since in vitro experimental conditions would allow for pharmacological as well as genetic manipulation, we tested whether similar activity changes could be observed in primary neurons cultured from the same genetic lines.…”

“…This sequence was placed under the control of an upstream activating sequence (UAS), such that the UAS-GAL4 system in Drosophila (Brand and Perrimon, 1993) can be used for tissue-specific expression of the UAS-Ab42 transgene (Iijima et al, 2008). Indeed, pan-neuronal expression of UAS-Ab42 with the elav-GAL4 driver (genotype: elav-GAL4;UAS-Ab42/+, also referred to as elav-GAL4>>UAS-Ab42) has been reported to induce extracellular amyloid deposits, age-dependent learning and locomotor defects, progressive neurodegeneration, and premature death (Finelli et al, 2004;Iijima et al, 2004Iijima et al, , 2008Ping et al, 2015). Since Drosophila central neurons are predominantly cholinergic, we use them as a model for how Ab42 affects cholinergic synaptic activity.…”

Modeling the complex pathology of Alzheimer's disease in Drosophila

“…A recent study also described the selective degradation of Kv4 channels in flies expressing Aβ42 leading to neuronal hyperactivity (Fig. 3) (Ping et al, 2015). Reducing the levels of Kv4 channels led to locomotor defects whereas Kv4 overexpression rescued Aβ42 neurotoxicity, supporting a critical role for K + channel activity in Aβ42 pathogenesis.…”

Mis-expression of the Alzheimer’s disease associated gene Ankyrin causes memory loss and shortened lifespan in Drosophila

“…In Drosophila, neuronal overexpression of different human APP products (including A42) and mutants has been reported to cause degeneration of the photoreceptor neurons of the fly eye, shortened lifespan, change in neuronal excitability as well as movement, circadian, sleep and learning defects in a number of different studies [26][27][28][29][30][31][32]. Likewise, neuronal overexpression of human Tau isoforms associated with AD have been shown to result in degeneration of the photoreceptor neurons of the fly eye, shortened lifespan, movement and learning defects in many different studies [33][34][35][36][37][38][39][40][41].…”