Comparative mapping of single-cell transcriptomic landscapes in neurodegenerative diseases.

Introduction: Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), and Parkinson's disease (PD) represent a spectrum of neurodegenerative disorders (NDDs). Here, we performed the first direct comparison of their transcriptomic landscapes.

Methods: We profiled the whole transcriptomes of NDD cortical tissue by snRNA-seq.

Microglia States are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD) but much less is known on the key cell types and pathways driving mechanisms of senescence in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed whole transcriptomic data and utilized single-cell RNA seq integration techniques to unveil the convoluted cell-type-specific and sub-cell-type-state-specific senescence pathologies in AD using both ROSMAP and Sea-AD datasets.

The therapeutic implications of all-in-one AAV-delivered epigenome-editing platform in neurodegenerative disorders.

Safely and efficiently controlling gene expression is a long-standing goal of biomedical research, and CRISPR/Cas system can be harnessed to create powerful tools for epigenetic editing. Adeno-associated-viruses (AAVs) represent the delivery vehicle of choice for therapeutic platform. However, their small packaging capacity isn't suitable for large constructs including most CRISPR/dCas9-effector vectors.

Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.

Introduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.

Single-nucleus multi-omics of Parkinson's disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks.

The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution.

All-in-one AAV-delivered epigenome-editing platform: and therapeutic implications for neurodegenerative disorders.

Safely and efficiently controlling gene expression is a long-standing goal of biomedical research, and the recently discovered bacterial CRISPR/Cas system can be harnessed to create powerful tools for epigenetic editing. Current state-of-the-art systems consist of a deactivated-Cas9 nuclease (dCas9) fused to one of several epigenetic effector motifs/domains, along with a guide RNA (gRNA) which defines the genomic target. Such systems have been used to safely and effectively silence or activate a specific gene target under a variety of circumstances.

Neuronal-type-specific epigenome editing to decrease expression: Implications for precision medicine in synucleinopathies.

Overexpression of has been implicated in the pathogenesis of synucleinopathies, particularly Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While PD and DLB share some clinical and pathological similarities, each disease presents distinct characteristics, including the primary affected brain region and neuronal type. We aimed to develop neuronal-type-specific -targeted epigenome therapies for synucleinopathies.

Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains.

Background: The genetic underpinnings of late-onset Alzheimer's disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD.

Bioinformatics pipeline to guide post-GWAS studies in Alzheimer's: A new catalogue of disease candidate short structural variants.

Background: Short structural variants (SSVs), including insertions/deletions (indels), are common in the human genome and impact disease risk. The role of SSVs in late-onset Alzheimer's disease (LOAD) has been understudied. In this study, we developed a bioinformatics pipeline of SSVs within LOAD-genome-wide association study (GWAS) regions to prioritize regulatory SSVs based on the strength of their predicted effect on transcription factor (TF) binding sites.

Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients.

Depression is common among late-onset Alzheimer's Disease (LOAD) patients. Only a few studies investigated the genetic variability underlying the comorbidity of depression in LOAD. Moreover, the epigenetic and transcriptomic factors that may contribute to comorbid depression in LOAD have yet to be studied.

Polygenic Risk Score Effectively Predicts Depression Onset in Alzheimer's Disease Based on Major Depressive Disorder Risk Variants.

Introduction: Depression is a common, though heterogenous, comorbidity in late-onset Alzheimer's Disease (LOAD) patients. In addition, individuals with depression are at greater risk to develop LOAD. In previous work, we demonstrated shared genetic etiology between depression and LOAD.

Bioinformatics pipeline to guide late-onset Alzheimer's disease (LOAD) post-GWAS studies: Prioritizing transcription regulatory variants within LOAD-associated regions.

Introduction: As new late-onset Alzheimer's disease (LOAD) genetic risk loci are identified and brain cell-type specific omics data becomes available, there is an unmet need for a bioinformatics framework to prioritize genes and variants for testing in single-cell molecular profiling experiments and validation using disease models and gene editing technologies. Prior work has characterized and prioritized active enhancers located in LOAD-genome-wide association study (GWAS) regions and their potential interactions with candidate genes. The current study extends this work by focusing on single nucleotide polymorphisms (SNPs) within these LOAD enhancers and their impact on altering transcription factor (TF) binding.

Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains.

Background: In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer's disease (LOAD) and translate the associations to causation.

Methods: We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner.

Results: We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP).

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets.

Cell-Type Specific Changes in DNA Methylation of Intron 1 in Synucleinopathy Brains.

Parkinson's disease (PD) and dementia with Lewy body (DLB) are the most common synucleinopathies. gene is a major genetic risk factor for these diseases group, and dysregulation of its expression has been implicated in the genetic etiologies of several synucleinopathies. DNA methylation at CpG island (CGI) within intron 1 has been suggested as a regulatory mechanism of expression, and changes in methylation levels at this region were associated with PD and DLB.

: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer's.

Alzheimer's disease (AD) has a critical unmet medical need. The consensus around the amyloid cascade hypothesis has been guiding pre-clinical and clinical research to focus mainly on targeting beta-amyloid for treating AD. Nevertheless, the vast majority of the clinical trials have repeatedly failed, prompting the urgent need to refocus on other targets and shifting the paradigm of AD drug development towards precision medicine.

The Path to Progress Preclinical Studies of Age-Related Neurodegenerative Diseases: A Perspective on Rodent and hiPSC-Derived Models.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent age-related neurodegenerative diseases, and currently no effective clinical treatments exist for either, despite decades of clinical trials. The failure to translate preclinical findings into effective treatments is indicative of a problem in the current evaluation pipeline for potential therapeutics. At present, there are no useful animal models for AD and PD research that reflect the entire biology of the diseases, specifically, the more common non-Mendelian forms.

Good problems to have? Policy and societal implications of a disease-modifying therapy for presymptomatic late-onset Alzheimer's disease.

In the United States alone, the prevalence of AD is expected to more than double from six million people in 2019 to nearly 14 million people in 2050. Meanwhile, the track record for developing treatments for AD has been marked by decades of failure. But recent progress in genetics, neuroscience and gene editing suggest that effective treatments could be on the horizon.

The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations.

Alpha-synuclein SNCA has been implicated in the etiology of Parkinson's disease (PD); however, the normal function of alpha-synuclein protein and the pathway that mediates its pathogenic effect is yet to be discovered. We investigated the mechanistic role of SNCA in the nucleus utilizing isogenic human-induced pluripotent stem cells-derived neurons from PD patients with autosomal dominant mutations, A53T and SNCA-triplication, and their corresponding corrected lines by genome- and epigenome-editing. Comparisons of shape and integrity of the nuclear envelope and its resistance to stresses found that both mutations result in similar nuclear envelope perturbations that were reversed in the isogenic mutation-corrected cells.

Gene-Editing Technologies Paired With Viral Vectors for Translational Research Into Neurodegenerative Diseases.

Diseases of the central nervous system (CNS) have historically been among the most difficult to treat using conventional pharmacological approaches. This is due to a confluence of factors, including the limited regenerative capacity and overall complexity of the brain, problems associated with repeated drug administration, and difficulties delivering drugs across the blood-brain barrier (BBB). Viral-mediated gene transfer represents an attractive alternative for the delivery of therapeutic cargo to the nervous system.

Sex-dependent effect of on Alzheimer's disease and other age-related neurodegenerative disorders.

The importance of apolipoprotein E () in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of to LOAD susceptibility.

Shared genetic etiology underlying late-onset Alzheimer's disease and posttraumatic stress syndrome.

Introduction: Late-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies.

Methods: We performed genetic pleiotropy analysis using LOAD and PTSD genome-wide association study (GWAS) datasets from white and African-American populations, followed by functional-genomic analyses.

Results: We found an enrichment for LOAD across increasingly stringent levels of significance with the PTSD GWAS association (LOAD|PTSD) in the discovery and replication cohorts and a modest enrichment for the reverse conditional association (PTSD|LOAD).

Shared genetic etiology underlying Alzheimer's disease and major depressive disorder.

Patients with late-onset Alzheimer's disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with major depressive disorder (MDD) have an increased prevalence of LOAD. This suggests shared etiologies and intersecting pathways between LOAD and MDD. We performed pleiotropy analyses using LOAD and MDD GWAS data sets from the International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium (PGC), respectively.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results.