Abstract
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by intracellular neurofibrillary tangles of hyperphosphorylated Tau, including the 0N4R isoform and accumulation of extracellular amyloid beta (Aβ) plaques. However, less than 5% of AD cases are familial, with many additional risk factors contributing to AD including aging, lifestyle, the environment and epigenetics. Recent epigenome-wide association studies (EWAS) of AD have identified a number of loci that are differentially methylated in the AD cortex. Indeed, hypermethylation and reduced expression of the Ankyrin 1 (ANK1) gene in AD has been reported in the cortex in numerous different post-mortem brain cohorts. Little is known about the normal function of ANK1 in the healthy brain, nor the role it may play in AD. We have generated Drosophila models to allow us to functionally characterize Drosophila Ank2, the ortholog of human ANK1 and to determine its interaction with human Tau and Aβ. We show expression of human Tau 0N4R or the oligomerizing Aβ 42 amino acid peptide caused shortened lifespan, degeneration, disrupted movement, memory loss, and decreased excitability of memory neurons with co-expression tending to make the pathology worse. We find that Drosophila with reduced neuronal Ank2 expression have shortened lifespan, reduced locomotion, reduced memory and reduced neuronal excitability similar to flies overexpressing either human Tau 0N4R or Aβ42. Therefore, we show that the mis-expression of Ank2 can drive disease relevant processes and phenocopy some features of AD. Therefore, we propose targeting human ANK1 may have therapeutic potential. This represents the first study to characterize an AD-relevant gene nominated from EWAS.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, with patients suffering from premature death and accelerated cognitive decline including memory loss
The reduction in median lifespan due to co-expression was equivalent to an additive effect of the shortening of life due to mutant amyloid precursor protein (APP) (Aβ42) and Memory and Lifespan associated protein Tau (MAPT) (0N4R) alone, this suggests that Aβ42 and Tau pathology may act in separate pathways to cause neurotoxicity and early death
We found reduction in expression of the fly ortholog of human Ankyrin 1 (ANK1), which is Drosophila Ank2, in areas of the brain responsible for memory, caused memory impairment similar in magnitude to that caused by overexpression of human mutant APP resulting in an oligomerizing form of Aβ42 or MAPT producing the 0N4R isoform of Tau, both of which are associated with the disease
Summary
Alzheimer’s disease (AD) is the most common form of dementia, with patients suffering from premature death and accelerated cognitive decline including memory loss. The 4R isoforms are upregulated in AD brain and show stronger tubulin binding and aggregation than the 3R isoforms (Arendt et al, 2016) Another contributing factor to Tau aggregation is its hyperphosphorylation by a number of different kinases including glycogen synthase kinase-3β, cyclindependent kinase 5, JNK, microtubule-associated regulatory kinase, DYRK1a and CaMKII (Hanger et al, 1992; Ferrer et al, 2005; Plattner et al, 2006; Wang et al, 2007; Dolan and Johnson, 2010; Ghosh and Giese, 2015). It is not currently known how Aβ and Tau pathology are linked, the amyloid cascade hypothesis suggests that Aβ pathology leads to the other hallmarks of AD, including the spread of NFTs (Selkoe and Hardy, 2016) and recent work suggests changes in neuronal excitability and calcium (Ca2+) signaling may be important for their connection and disease progression (SpiresJones and Hyman, 2014; Wu et al, 2016), but exactly how remains unknown
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