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Multiple neurological, physiological, and behavioral functions are synchronized by circadian clocks into daily rhythms. Neurodegenerative diseases such as Alzheimer's disease and related tauopathies are associated with a decay of circadian rhythms, disruption of sleep patterns, and impaired cognitive function but the mechanisms underlying these alterations are still unclear. Traditional approaches in neurodegeneration research have focused on understanding how pathology impinges on circadian function. Since in Alzheimer's disease and related tauopathies tau proteostasis is compromised, here we sought to understand the role of tau protein in neuronal circadian biology and related behavior. Considering molecular mechanisms underlying circadian rhythms are conserved from Drosophila to humans, here we took advantage of a recently developed tau-deficient Drosophila line to show that loss of tau promotes dysregulation of daily circadian rhythms and sleep patterns. Strikingly, tau deficiency dysregulates the structural plasticity of the small ventral lateral circadian pacemaker neurons by disrupting the temporal cytoskeletal remodeling of its dorsal axonal projections and by inducing a slight increase in the cytoplasmic accumulation of core clock proteins. Taken together, these results suggest that loss of tau function participates in the regulation of circadian rhythms by modulating the correct operation and connectivity of core circadian networks and related behavior.

Intracellular accumulation of hyperphosphorylated misfolded tau proteins is one of the main neuropathological hallmarks in Alzheimer’s disease (AD) and related tauopathies. Hence, knowledge and understanding of disease mechanisms altering tau proteostasis and inducing cytotoxicity is critical. MicroRNAs (miRNAs) are capable of binding to and silencing many target transcripts, providing an additional level of regulation that complements canonical transcriptional pathways. Therefore, observed abnormalities in their expression patterns in neurodegeneration suggest alterations of microRNA-target networks as drivers of cellular dysfunction in the disease. Strikingly, here we have found in autopsy brain tissue that miRNA miR-219 expression levels are decreased in a brain region early affected in AD patients, the entorhinal cortex. Our bioinformatics analysis indicates miR-219 is predicted to target Calcium/calmodulin-dependent protein kinase 2 gamma subunit (CAMK2γ), Tau tubulin kinase 1 (TTBK1) and Glycogen synthase kinase 3 beta (GSK3β), which are all implicated in the generation of abnormal hyperphosphorylated tau. We reveal human proteomic data supporting dysregulation in the levels of predicted miR-219 targets in the entorhinal cortex. In mammalian cellular models, we found that downregulation of miR-219 de-repress synthesis of three tau kinases, CAMK2γ, TTBK1 and GSK3β on the post-transcriptional level resulting in tau phosphorylation and cell toxicity. Finally, we show that deficiency of miR-219 in vivo promotes age dependent neurodegeneration in the adult brain, with enhanced alterations in tau proteostasis, presynaptic terminals and memory impairment. Taken together, our data implicate miRNA dysregulation central to AD etiopathogenesis and suggest potential targets for the treatment of AD and related tauopathies.

ObjectiveSynonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation.MethodsTo detect synonymous variants modulating AD risk, we conducted a whole-genome sequencing study on 67 Caribbean Hispanic (CH) families multiply affected by AD. Identified disease-associated variants were further assessed in an independent cohort of CHs, expression quantitative trait locus (eQTL) data, brain autopsy data, and functional experiments.ResultsRare synonymous variants in 4 genes (CDH23, SLC9A3R1, RHBDD2,andITIH2) segregated with AD status in multiplex families and had a significantly higher frequency in these families compared with reference populations of similar ancestry. In comparison to subjects without dementia, expression ofCDH23(β = 0.53,p= 0.006) andSLC9A3R1(β = 0.50,p= 0.02) was increased, and expression ofRHBDD2(β = −0.70,p= 0.02) decreased in individuals with AD at death. In line with this finding, increased expression ofCDH23(β = 0.26 ± 0.08,p= 4.9E-4) and decreased expression ofRHBDD2(β = −0.60 ± 0.12,p= 5.5E-7) were related to brain amyloid load (p= 0.0025).SLC9A3R1expression was associated with burden of TDP43 pathology (β = 0.58 ± 0.17,p= 5.9E-4). Using eQTL data, theCDH23variant was in linkage disequilibrium with variants modulatingCDH23expression levels (top single nucleotide polymorphism: rs11000035,p= 4.85E-6, D' = 1.0). Using minigene splicing assays, theCDH23andSLC9A3R1variants affected splicing efficiency.ConclusionsThese findings suggest thatCDH23, SLC9A3R1, RHBDD2, and possiblyITIH2, which are involved in synaptic function, the glutamatergic system, and innate immunity, contribute to AD etiology. In addition, this study supports the notion that synonymous variants contribute to AD risk and that comprehensive scrutinization of this type of genetic variation is warranted and critical.