Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β

Chai, Amanda B.; Lam, Hin Hei Julian; Kockx, Maaike; Gelissen, Ingrid C.

doi:10.1016/j.bbalip.2021.158980

Cited by 17 publications

(12 citation statements)

References 174 publications

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“…Concerning their genetics, previous investigations showed that the two cases carried the ApoE ε4 allele, which is known to increase the risk of developing AD of 3-4-fold [25,26]. Indeed, both showed a severe cortical amyloid load with amyloid angiopathy [27]. However, through NGS we found no pathogenic variants in the causative genes known to be involved in AD and LBD.…”

Section: Discussionmentioning

confidence: 62%

Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

Palmieri

Poloni

Medici

et al. 2022

Preprint

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Background Alzheimer’s disease (AD) and Lewy body dementia (LBD) are two different forms of dementia, but their pathology may involve the same cortical areas with overlapping cognitive manifestation. Dementia cases within the same family share a common genetic background. Nonetheless, the clinical phenotype may be different due to the different underlying molecular processes that come up apart from genetics, causing diverse neurodegeneration. The aim of this study was to define commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed a classical AD and an aggressive form of AD/LBD respectively, through neuropathological, genetic and transcriptomic comparison of four different brain areas (substantia nigra, hippocampus, parietal lobe and basal ganglia). Results Genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in LBD pathology, while AD underwent lower degree of transcriptional dysregulation, with the parietal lobe being the most involved brain area. Conversely, hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Conclusions Our data suggest that there is a link between the transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis.

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Section: Discussionmentioning

confidence: 62%

Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

Palmieri

Poloni

Medici

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Concerning their genetics, previous investigations showed that the two cases carried the ApoE ε4 allele, which is known to increase the risk of developing AD three to four-fold [ 47 , 48 ]. Accordingly, both showed a severe cortical amyloid load with amyloid angiopathy [ 49 ]. Interestingly, the ApoE ε4 allele has been also described as a potential genetic modifier of the age at onset, conferring anticipation through generations [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

Palmieri¹,

Poloni

Medici

et al. 2022

Biomedicines

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Alzheimer’s disease (AD) and Lewy body dementia (LBD) are two different forms of dementia, but their pathology may involve the same cortical areas with overlapping cognitive manifestations. Nonetheless, the clinical phenotype is different due to the topography of the lesions driven by the different underlying molecular processes that arise apart from genetics, causing diverse neurodegeneration. Here, we define the commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed classical AD and an aggressive form of AD/LBD, respectively, through a neuropathological, genetic (next-generation sequencing), and transcriptomic (RNA-seq) comparison of four different brain areas. A genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in the AD/LBD case, while the AD case showed lower transcriptional dysregulation, with the parietal lobe being the most involved brain area. The hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Our data suggest that there is a link between transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis.

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“…APOE4 alters the baseline pro-inflammatory response even in the absence of disease, suggesting that APOE4 may indeed cause dysfunctional inflammatory responses that trigger neurodegeneration [ 61 – 63 ]. Furthermore, APOE4 is correlated with dysfunctional microglial clearance of Aβ [ 64 ]. Although the majority of people carrying the APOE4 genetic variant have an enhanced predisposition for AD, the effect size is lower or absent in populations of people with African ancestry compared with Europeans or Chinese [ 65 ].…”

Section: Main Textmentioning

confidence: 99%

Solving neurodegeneration: common mechanisms and strategies for new treatments

Wareham

Liddelow²,

Temple

et al. 2022

Mol Neurodegeneration

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Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled “Solving Neurodegeneration”. This “think-tank” style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world’s leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.

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Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β

Cited by 17 publications

References 174 publications

Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

Solving neurodegeneration: common mechanisms and strategies for new treatments

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