ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias

Martens, Yuka A.; Zhao, Na; Liu, Chia-Chen; Kanekiyo, Takahisa; Yang, Austin J.; Goate, Alison; Holtzman, David M.; Bu, Guojun

doi:10.1016/j.neuron.2022.03.004

Cited by 184 publications

(115 citation statements)

References 161 publications

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“…The APOE E4 allele is the strongest genetic risk factor for sporadic Alzheimer’s disease and APOE, along with amyloidogenic processing of the amyloid precursor protein (APP) into Aβ, is thought of as an initiating and driving factor in disease etiology (Frisoni et al, 2022; Huang and Mahley, 2014; Martens et al, 2022). While mitochondrial dysfunction is acknowledged as an important factor in Alzheimer’s disease, mitochondria are typically placed downstream of Aβ and APOE, with Aβ or the APOE4 allele perturbing mitochondrial function (Area-Gomez et al, 2020; Chen et al, 2011; Huang et al, 2020; Orr et al, 2019; Tambini et al, 2016; Yin et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction

Wynne

Ogunbona

Lane

et al. 2022

Preprint

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Mitochondria are dynamic organelles that influence cellular function through both cell- autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the inner mitochondrial membrane caused upregulation of the Alzheimer’s disease risk factor apolipoprotein E (APOE) and other secretome components. This upregulation of secretory proteins was of a similar extent as modifications to the mitochondrial annotated proteome. Gene editing of SLC25A family inner mitochondrial membrane transporters, as well as genetic and pharmacological disruption of copper-dependent and independent steps of electron transport chain assembly and function, caused upregulation of APOE transcript, protein, and secretion, up to 16-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC- derived human astrocytes as part of an inflammatory gene expression program. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.

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Section: Discussionmentioning

confidence: 99%

APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction

Wynne

Ogunbona

Lane

et al. 2022

Preprint

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“…Genetic, model system and neuropathology studies have clearly established Aβ, tau and APOE as disease hallmarks, biomarkers and therapeutic targets in AD and other neurodegenerative diseases [63][64][65] . Even though there are several strategies targeting these molecules for therapeutic benefit in AD, there are critical knowledge gaps that hinder progress.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins

Oatman

Reddy

Quicksall

et al. 2022

Preprint

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Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Main protein components of these hallmarks include Aβ40, Aβ42, tau, phospho-tau and APOE. With the exception of the APOE-ϵ4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

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“…In addition to the multitude of astrocytic metabolic pathways that impact neuronal health, cytokines secreted by glial cells also influence neuron metabolism 30 . APOE4 is thought to increase AD risk through several mechanisms, including by altering immune signaling networks 31 . Importantly, immune signaling involves many interacting pathways, necessitating multivariate analysis to properly account for interaction and covariation of cytokine pathways.…”

Section: Apoe4 Astrocytes Do Not Respond To Aβ Stimulation With Chang...mentioning

confidence: 99%

Apolipoprotein E4 modulates astrocyte neuronal support functions in the presence of amyloid-β

Fleeman

Kuhn

Chan

et al. 2022

Preprint

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Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ϵ4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimers disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism. Astrocytes provide various forms of support to neurons, including regulating neuron metabolism and immune responses through cytokine signaling. Changes in astrocyte function due to APOE4 may therefore decrease neuronal support, leaving neurons more vulnerable to stress and disease insults. To determine whether APOE4 alters astrocyte neuronal support functions, we measured glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk-neutral variant) primary astrocyte cultures. We found that APOE4 neurons treated with conditioned media from resting APOE4 astrocytes had similar metabolism to APOE3 astrocytes, but treatment with ACM from astrocytes challenged with amyloid-β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not due to differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion response to Aβ. Together, these findings suggest that in the presence of Aβ, APOE4 astrocytes alter immune and metabolic functions that result in a compensatory increase in neuronal metabolic stress.

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ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias

Cited by 184 publications

References 161 publications

APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction

APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins

Apolipoprotein E4 modulates astrocyte neuronal support functions in the presence of amyloid-β

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