Late-onset Alzheimer's Disease Brain Research Articles

Multiomics Analyses Identify Proline Endopeptidase-Like Protein As a Key Regulator of Protein Trafficking, a Pathway Underlying Alzheimer's Disease Pathogenesis.

Current treatments for Alzheimer's disease (AD) help reduce symptoms for a limited time but do not treat the underlying pathology. To identify potential therapeutic targets for AD, an integrative network analysis was previously carried out using 364 human postmortem control, mild cognitive impairment, and AD brains. This analysis identified proline endopeptidase-like protein (PREPL), an understudied protein, as a downregulated protein in late-onset AD patients. In this study we investigate the role of PREPL. Analyses of data from human postmortem samples and PREPL knockdown (KD) cells suggest that PREPL expression modulates pathways associated with protein trafficking, synaptic activities, and lipid metabolism. Furthermore, PREPL KD impairs cell proliferation and modulates the structure of vesicles, levels of neuropeptide-processing enzymes, and secretion of neuropeptides. In addition, decrease in PREPL levels leads to changes in the levels of a number of synaptic proteins as well as changes in the levels of secreted amyloid beta (Aβ) 42 peptide and Tau phosphorylation. Finally, we report that local decrease in PREPL levels in mouse hippocampus attenuates long-term potentiation, suggesting a role in synaptic plasticity. Together, our results indicate that PREPL affects neuronal function by modulating protein trafficking and synaptic function, an important mechanism of AD pathogenesis. SIGNIFICANCE STATEMENT: Integrative network analysis reveals proline endopeptidase-like protein (PREPL) to be downregulated in human sporadic late-onset Alzheimer's disease brains. Down regulation of PREPL leads to increases in amyloid beta secretion, Tau phosphorylation, and decreases in protein trafficking and long-term potentiation.

Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer's disease brains.

The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.

Parallel single-nucleus chromatin accessibility and transcriptomic profiling of human late-onset Alzheimer's disease brains.

In the post-GWAS era for late-onset Alzheimer's disease (LOAD), the precise disease-causing genes, the specific causal variants, and molecular mechanisms mediating their pathogenic effects remain unknown. Recent studies using single-nucleus (sn)RNA-seq on human LOAD tissue have achieved unprecedented resolution in identifying cell type-specific gene dysregulation, however the regulatory mechanisms and genetic variability underlying these LOAD-specific transcriptomic signatures remain to be identified. Nuclei were isolated from frozen post-mortem human temporal cortex tissue from LOAD patients and cognitively healthy controls (n = 24, all Caucasian and APOE 3/3). 10X Genomics technology was used to generate single-nucleus (sn)RNA-seq and snATAC-seq libraries in parallel from the same pool of nuclei isolated from each brain sample. Uniform manifold approximation and projection (UMAP) analysis showed a total of 29 clusters assigned to 8 cell types including astrocytes, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) in both snRNA-seq and snATAC-seq datasets. We identified differentially expressed genes (DEGs) and differentially accessible peaks (DAPs) for each cluster and found overlaps with known LOAD GWAS regions (SNP+/- 1Mb) as well as new LOAD loci that were not discovered previously. We next performed co-accessibility analysis and identified co-accessible peaks that were more open in LOAD and corresponded to dysregulation of nearby target genes. This analysis also produced networks of co-accessible LOAD peaks that were enriched in transcription factor (TF) motifs of TFs that are specifically overexpressed in LOAD samples. Integrative multi-omics is a powerful strategy to identify regulatory elements underlying gene dysregulation in LOAD. By integrating single-nucleus transcriptomic and open chromatin profiles from the same pool of nuclei, we are able to identify cell subtype-specific molecular mechanisms contributing to LOAD pathogenesis. This new genetic knowledge will progress the identification of new therapeutic targets.

Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease

Alzheimer's disease (AD) is strongly associated with microglia-induced neuroinflammation. Particularly, Aβ plaque-associated microglia take on an “activated” morphology. However, the function and phenotype of these Aβ plaque-associated microglia are not well understood. We show hyperreactivity of Aβ plaque-associated microglia upon systemic inflammation in transgenic AD mouse models (i.e., 5XFAD and APP23). Gene expression profiling of Aβ plaque-associated microglia (major histocompatibility complex II+ microglia) isolated from 5XFAD mice revealed a proinflammatory phenotype. The upregulated genes involved in the biological processes (gene ontology terms) included: “immune response to external stimulus” such as Axl, Cd63, Egr2, and Lgals3, “cell motility”, such as Ccl3, Ccl4, Cxcr4, and Sdc3, “cell differentiation”, and “system development”, such as St14, Trpm1, and Spp1. In human AD tissue with similar Braak stages, expression of phagocytic markers and AD-associated genes, including HLA-DRA, APOE, AXL, TREM2, and TYROBP, was higher in laser-captured early-onset AD (EOAD) plaques than in late-onset AD plaques. Interestingly, the nonplaque parenchyma of both EOAD and late-onset AD brains, the expression of above-mentioned markers were similarly low. Here, we provide evidence that Aβ plaque-associated microglia are hyperreactive in their immune response and phagocytosis in the transgenic AD mice as well as in EOAD brain tissue. We suggest that Aβ plaque-associated microglia are the primary source of neuroinflammation related to AD pathology.

Regional quantitative study of formation process of neurofibrillary tangles in the hippocampus of non-demented elderly brains: Comparison with late-onset Alzheimer's disease brains

Regional quantitative study of formation process of neurofibrillary tangles in the hippocampus of non-demented elderly brains: Comparison with late-onset Alzheimer's disease brains