The list of developmental and degenerative diseases that are caused by expansion of unstable repeats continues to grow, and is now approaching 20 disorders. The pathogenic mechanisms that underlie these disorders involve either loss of protein function or gain of function at the protein or RNA level. Common themes have emerged within and between these different classes of disease; for example, among disorders that are caused by gain-of-function mechanisms, altered protein conformations are central to pathogenesis, leading to changes in protein activity or abundance. In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes.

Introduction Sensitive detection of cognitive decline over the course of preclinical Alzheimer’s disease is critical as the field moves toward secondary prevention trials. Methods We examined Aβ-related change in several variations of the preclinical Alzheimer cognitive composite (PACC) and each individual PACC component in clinically normal (CN) older participants in the Harvard Aging Brain Study. We then examined the PACC variations in the Alzheimer’s Disease Cooperative Study Prevention Instrument Study as a replication cohort. Results Aβ+ CN individuals demonstrated longitudinal decline on all individual PACC components and all PACC variations. Aβ group differences emerged earlier when Free and Cued Selective Reminding Test Free Recall was included in the PACC. PACC decline was associated with Clinical Dementia Rating progression. Discussion This independent data set and a replication cohort confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages of Alzheimer’s disease, which may prove advantageous in the prevention trial design.

Objectives: Amyloid-beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. Methods: One hundred thirty-seven older individuals (age = 76.3 AE 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ ( 11 C-Pittsburgh compound B) and tau ( 18 F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 AE 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. Results: Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. Interpretation: Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD.

Calcium-calmodulin-dependent kinase II (CaMKII) has a long history of involvement in synaptic plasticity, yet little focus has been given to potassium channels as CaMKII targets despite their importance in repolarizing EPSPs and action potentials and regulating neuronal membrane excitability. We now show that Kv4.2 acts as a substrate for CaMKII in vitro and have identified CaMKII phosphorylation sites as Ser438 and Ser459. To test whether CaMKII phosphorylation of Kv4.2 affects channel biophysics, we expressed wild-type or mutant Kv4.2 and the K ϩ channel interacting protein, KChIP3, with or without a constitutively active form of CaMKII in Xenopus oocytes and measured the voltage dependence of activation and inactivation in each of these conditions. CaMKII phosphorylation had no effect on channel biophysical properties. However, we found that levels of Kv4.2 protein are increased with CaMKII phosphorylation in transfected COS cells, an effect attributable to direct channel phosphorylation based on site-directed mutagenesis studies. We also obtained corroborating physiological data showing increased surface A-type channel expression as revealed by increases in peak K ϩ current amplitudes with CaMKII phosphorylation. Furthermore, endogenous A-currents in hippocampal pyramidal neurons were increased in amplitude after introduction of constitutively active CaMKII, which results in a decrease in neuronal excitability in response to current injections. Thus CaMKII can directly modulate neuronal excitability by increasing cell-surface expression of A-type K ϩ channels.

Spinocerebellar ataxia type 1 is caused by expansion of a translated CAG repeat in ataxin1. The level of the polyglutamine-expanded protein is one of the factors that contribute to disease severity. Here, we show that miR-19, miR-101, and miR-130 co-regulate ataxin1 levels and that their inhibition enhances the cytotoxicity of polyglutamine-expanded ataxin1. This study provides a new candidate mechanism for modulating pathogenesis of neurodegenerative diseases sensitive to protein dosage.Polyglutamine (polyQ) diseases are dominantly inherited, neurodegenerative disorders caused by expansion of CAG repeats that encode polyglutamine in the disease causing protein. In all these disorders, the polyQ-expanded proteins are toxic, leading to degeneration of specific neurons. Although animal studies have shown that levels of the mutant protein contribute to polyQ disease severity 4,5,6,7 , the in vivo mechanisms that regulate protein levels remain to be addressed.To verify that mutant protein levels contribute to disease severity in the context of SCA1, we evaluated mice that overexpress SCA1 (ATXN1) with 82 CAG repeats under the control of the Purkinje cell-specific Pcp2 promoter (SCA1[82Q]) 4 either in hemizgous or homozygous state. SCA1[82Q]Tg/Tg mice show more severe motor impairment and Purkinje cell pathology compared to SCA1[82Q] Tg/+ mice ( Supplementary Fig. 1a,b). These data suggest that increased levels of mutant protein result in more severe disease.Human ATXN1 contains a long 3´UTR (~7kb), implying that it might contain regulatory elements for posttranscriptional regulation ( Fig. 1f and Supplementary Fig. 5a). One mechanism that regulates levels of gene products involves microRNAs (miRNAs), endogenous small non-coding RNAs that bind the 3´UTR of cognate target mRNAs to suppress their To test this hypothesis, we searched for evolutionarily conserved miRNA binding sites in the 3´UTR of human ATXN1 using miRNA target prediction databases 10,11 . Of the predicted miRNAs, we chose eight different miRNAs as candidates, based on the number of ATXN1 target sites and their neuronal expression. To validate the role of the selected miRNAs in modulating ATXN1 levels, we transfected MCF7 cells, which highly express endogenous ATXN1 ( Supplementary Fig. 2a), with each miRNA duplex. miR-19a, miR-101, and miR-130a down-regulated the level of ATXN1 (Supplementary Fig. 2b). Generally, different miRNAs act cooperatively on the same target mRNA to suppress its translation 8 . To determine if this is the case for the miRNAs we identified, we transfected different human cell lines (HEK293T, HeLa, and MCF7 cells) either with each individual miRNA (miR-19a, miR-101, and miR-130a) or with all of them combined. We observed a marked decrease in ATXN1 levels upon co-transfection of all three miRNAs; transfection of 120 pmoles of each miRNA individually also decreased ATXN1 levels (Fig. 1a,b and Supplementary Fig. 3a-c). When we used 40 pmoles for each individual miRNA, the reduction in ATXN1 levels was less pronounced in c...

Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Higher amyloid beta burden was associated with increasing anxious-depressive symptoms over time in cognitively normal older individuals. Prior depression history was related to higher but not worsening symptom ratings. These results suggest a direct or indirect association of elevated amyloid beta levels with worsening anxious-depressive symptoms and support the hypothesis that emerging neuropsychiatric symptoms represent an early manifestation of preclinical Alzheimer's disease.

BackgroundSpinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1154Q/2Q mice) that replicates many features of the human disease.Methods and Findings Sca1154Q/2Q mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1154Q/2Q mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity.ConclusionsThe effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.