Biology subjects

Aarsland, D.

Publications and source records attributed to Aarsland, D..

9 recordsLinked to original sources

bioRxiv2025

Synaptotoxic forms of amyloid-b and a-synuclein act through a common pathway.

It has been suggested that -synuclein (Syn), a major player in Parkinsons disease (PD), plays a role in Alzheimers disease (AD). Several reports have also concluded that Syn and amyloid-{beta} (A{beta}) are mechanistically linked, although how is unclear. Synapse loss is an early feature in both PD and AD and held to be the driver of both diseases. We have previously uncovered a signalling pathway required for A{beta}-driven dendritic spine loss - a non-canonical branch of Wnt signalling known as the Wnt/Planar Cell Polarity (Wnt/PCP) pathway. We asked if a synaptotoxic form of Syn known to impact dendritic spines, the A53T autosomal dominant PD mutant form of Syn (A53T-Syn), might act on synapses through the same pathway. Here, by blocking all Wnt activity with the porcupine inhibitor IWP2, we show that A53T-Syn-driven spine loss is Wnt-dependent. By silencing Daam1, which is unique to Wnt/PCP, we show that A53T-Syn spine loss is Daam1-dependent. Finally, using the pan-ROCK inhibitor fasudil indicates the mechanism also involves ROCK1/2, which Daam1 signals to via RhoA to modulate actin cytoskeletal dynamics within dendritic spines. Together, these observations indicate that A53T-Syn-driven spine loss involves the Wnt/PCP pathway, the same pathway that mediates A{beta} synaptotoxicity. This indicates that A{beta} and Syn are mechanistically connected and that a common pathway is responsible for synapse loss in AD and PD. It also begins to explain why this group of neurodegenerative diseases have many features in common and suggests that drugs which target Wnt/PCP could be of benefit for both AD and PD.

neuroscience↗

bioRxiv2025

Transcription driven repurposing of cardiotonic steroids for Lithium treatment of severe depression

Lithium is prescribed as a mood stabiliser in bipolar disorder and severe depression. However, the mechanism of action of Lithium is unknown and there are major side effects associated with prolonged medication. This motivates a search for safer alternative drug repurposing candidates. Given that the drug mechanism may be encoded in transcriptional changes we have generated the gene expression profile for acute Lithium treatment of cortical neuronal cultures. We found that the Lithium associated transcription response harbours a significant component that is the reverse of that seen in human brain samples from patients with Major Depression, Bipolar Disorder and a mouse model of depression. Interrogating publicly available drug driven expression data we found that cardiotonic steroids drive gene expression in a correlated manner to our acute Lithium profile. An analysis of the psychiatric medication cohort of the Norwegian Prescription Database showed that cardiotonic prescription is associated with a lower incidence of lithium prescription. Our transcriptional and epidemiological observations point towards cardiotonic steroids as possible repurposing candidates for Lithium. These observations motivate a controlled trial to establish a causal connection and genuine therapeutic benefit in the context of depression.

neuroscience↗

bioRxiv2022

Neuroanatomical substrates in Parkinson's Disease psychosis and their association with serotonergic receptor gene expression: A coordinate-based meta-regression analysis.

BackgroundCommon neural underpinning of Parkinsons Disease (PD) psychosis across different structural magnetic resonance imaging (MRI) studies remains unclear to this day with few studies and even fewer meta-analyses available. ObjectivesOur meta-analysis aimed to identify and summarise studies using MRI approach to identify PD psychosis-specific brain regions and examine the relation between cortical volume loss and dopaminergic and serotonergic receptor density. MethodsPubMed, Web of Science and Embase were searched for MRI studies of PD psychosis (PDP) compared to PD patients without psychosis (PDnP). Seed-based d Mapping with Permutation of Subject Images was applied in the meta-analysis where coordinates were available. Multiple linear regressions to examine the relationship between grey matter volume loss in PDP and receptor gene expression density (extracted from the Allen Human Brain Atlas) were conducted in R. ResultsWe observed lower grey matter volume in parietal-temporo-occipital regions from our meta-analysis (N studies =10, PDP n=211, PDnP, n=298). These results remained significant after adjusting for PD medications and for cognitive scores. Grey matter volume loss in PDP was associated with local expression of 5-HT1a (b=0.109, p=0.012) and 5-HT2a receptors (b=-0.106, p=0.002) also after adjusting for PD medications (5-HT1a, p = 0.005; 5-HT2a, p = 0.001). ConclusionsWidespread cortical volume loss in the parieto-temporo-occipital regions involved in information processing and integration, as well as attention, could result in PD psychosis symptoms. Neurobiological mechanisms implicating serotonergic receptors may also contribute to this condition.

neuroscience↗

bioRxiv2022

Neurodegenerative disease associated pathways in brain of the triple transgenic Alzheimer's model are reversed in vivo following two weeks peripheral administration of fasudil

The pan ROCK inhibitor fasudil acts as a vasodilator and has been used as a medication post cerebral stroke for the past 27 years in Japan and China. More recently, on the basis of the involvement of ROCK inhibition on synaptic function, neuronal survival and processes associated with neuroinflammation, it has been suggested that the drug may be repurposed for neurodegenerative diseases. Indeed, fasudil has demonstrated preclinical efficacy in many neurodegenerative disease models. To facilitate an understanding of the wider biological processes at play due to ROCK inhibition in the context of neurodegeneration we performed a global gene expression analysis on the brains of Alzheimers disease model mice treated with fasudil via peripheral i.p injection. Our results show that fasudil tends to drive gene expression in a reverse sense to that seen in postmortem neurodegenerative disease brains. The results are most striking in terms of pathway enrichment analysis where pathways regulated in Alzheimers disease and by fasudil treatment are overwhelmingly regulated in opposite directions. Thus, our results bolster the repurposing potential of fasudil by demonstrating an anti-neurodegenerative phenotype in a disease context and highlight the potential of in vivo transcriptional profiling of drug activity.

neuroscience↗

bioRxiv2021

Validity and cultural generalisability of a 5-minute AI-based, computerised cognitive assessment in Mild Cognitive Impairment and Alzheimer's Dementia

INTRODUCTIONEarly detection and monitoring of mild cognitive impairment (MCI) and Alzheimers Disease (AD) patients are key to tackling dementia and providing benefits to patients, caregivers, healthcare providers and society. We developed the Integrated Cognitive Assessment (ICA); a 5-minute, language independent computerised cognitive test that employs an Artificial Intelligence (AI) model to improve its accuracy in detecting cognitive impairment. In this study, we aimed to evaluate the generalisability of the ICA in detecting cognitive impairment in MCI and mild AD patients. METHODSWe studied the ICA in a total of 230 participants. 95 healthy volunteers, 80 MCI, and 55 participants with mild AD completed the ICA, the Montreal Cognitive Assessment (MoCA) and Addenbrookes Cognitive Examination (ACE) cognitive tests. RESULTSThe ICA demonstrated convergent validity with MoCA (Pearson r = 0.58, p<0.0001) and ACE (r = 0.62, p<0.0001). The ICA AI model was able to detect cognitive impairment with an AUC of 81% for MCI patients, and 88% for mild AD patients. The AI model demonstrated improved performance with increased training data and showed generalisability in performance from one population to another. The ICA correlation of 0.17 (p=0.01) with education years is considerably smaller than that of MoCA (r=0.34, p<0.0001) and ACE (r=0.41, p<0.0001) which displayed significant correlations. In a separate study the ICA demonstrated no significant practice effect observed over the duration of the study. DISCUSSIONThe ICA can support clinicians by aiding accurate diagnosis of MCI and AD and is appropriate for large-scale screening of cognitive impairment. The ICA is unbiased by differences in language, culture and education.

neuroscience↗

bioRxiv2020

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration

Alpha-synuclein (-syn) mislocalisation and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinsons disease, Parkinsons disease with Dementia and Dementia with Lewy Bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying -syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human -syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, Cysteine String Protein, Synapsin, and Syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These -syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of Dementia with Lewy Bodies. Together, these findings demonstrate that presynaptic accumulation of -syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that -syn mediated synaptopathy is an initiating cause of age-related neurodegeneration.

neuroscience↗

bioRxiv2020

Integrated lipidomics and proteomics network analysis highlights lipid and immunity pathways associated with Alzheimer's disease

INTRODUCTIONThere is an urgent need to understand the molecular mechanisms underlying Alzheimers Disease (AD) to enable early diagnosis and develop effective treatments. Here we aim to investigate Alzheimers dementia using an unsupervised lipid, protein and gene multi-omic integrative approach. METHODSA lipidomics dataset (185 AD, 40 MCI and 185 controls) and a proteomics dataset (201 AD patients, 104 MCI individuals and 97 controls) were utilised for weighted gene co-expression network analyses (WGCNA). An additional proteomics dataset (94 AD, 55 MCI and 100 controls) was included for external proteomics validation. Modules created within each modality were correlated with clinical AD diagnosis, brain atrophy measures and disease progression, as well as with each other. Gene Ontology (GO) enrichment analysis was employed to examine the biological processes and molecular and cellular functions for protein modules associated with AD phenotypes. Lipid species were annotated in the lipid modules associated with AD phenotypes. Associations between established AD risk loci and lipid/protein modules that showed high correlation with AD phenotypes were also explored. RESULTSFive of the 20 identified lipid modules and five of the 17 identified protein modules were correlated with AD phenotypes. Lipid modules comprising of phospholipids, triglycerides, sphingolipids and cholesterol esters, correlated with AD risk loci involved in immune response and lipid metabolism. Five protein modules involved in positive regulation of cytokine production, neutrophil mediated immunity, humoral immune responses were correlated with AD risk loci involved in immune and complement systems. DISCUSSIONWe have shown the first multi-omic study linking genes, proteins and lipids to study pathway dysregulation in AD. Results identified modules of tightly regulated lipids and proteins that were strongly associated with AD phenotypes and could be pathology drivers in lipid homeostasis and innate immunity. Research in ContextO_LILipid and protein modules were preserved amongst Alzheimers disease (AD) patients, participants with mild cognitive impairment (MCI) and controls. Protein modules were also externally validated. C_LIO_LIFive lipid and five protein modules out of a total of thirty-seven correlated with clinical AD diagnosis, brain atrophy measurements and the rate of cognitive decline in AD. C_LIO_LILipid and protein modules associated with AD phenotypes showed associations with established AD risk loci involved in lipid and immune pathways. C_LI

neuroscience↗

bioRxiv2019

Association between schizophrenia polygenic score and psychotic symptoms in Alzheimer disease: meta-analysis of 10 cohort studies

BackgroundPsychosis (delusions and hallucinations) is common in Alzheimers disease (AD) and associated with worse clinical outcomes including accelerated cognitive decline and shorter time to nursing home admission. Atypical antipsychotics have limited efficacy which, along with emerging genomic research, suggests some overlapping mechanisms with other disorders characterized by psychosis, like schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with psychotic symptoms in AD. MethodsSchizophrenia PRS was calculated using Psychiatric Genomics Consortium data at 10 GWAS p-value thresholds (PT) in 3,173 AD cases from 11 cohort studies. Association between PRS and AD psychosis status was tested by logistic regression in each cohort individually and the results meta-analyzed. ResultsThe schizophrenia PRS was associated with psychosis in AD at an optimum PT of The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.17-fold increased risk (95% CI: 1.07-1.3; p=0.001). ConclusionThese new findings point towards psychosis in AD - and particularly delusions - sharing some genetic liability with schizophrenia, and support a transdiagnostic view of psychotic symptoms across the lifespan.

genomics↗

bioRxiv2018

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer’s disease risk

Late onset Alzheimers disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

genetics↗