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ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models
Open accessAbstract
Reversing Decline?: Apolipoprotein E (apoE) normally helps in the clearance of β-amyloid from the brain, a process that is compromised in Alzheimer's disease. Cramer et al. (p. 1503 , published online 9 February; see the Perspective by Strittmatter ) now show that a drug that increases apoE expression rapidly promoted soluble β-amyloid clearance in a mouse model of Alzheimer's disease. The drug also improved cognitive, social, and olfactory performance and rapidly improved neural circuit function. Similar therapeutics may potentially help to ameliorate the symptoms of Alzheimer's disease and its prodromal states.
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“Several groups have reported that trans-BBB efflux of Aβ into peripheral blood circulation is one of the main pathways of physiological clearance with ApoE, ApoJ, and ApoA1 as chaperones27,31,32.”
From Brain-targeted drug delivery by manipulating protein corona functions (2019) · cites this paper as [32]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“bexarotene (an RXR agonist) increases apoE levels”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [76]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Several studies demonstrated that treatment of LXR/RXR agonists increase the levels of ABCA1 and APOE and decrease amyloid deposition in APP overexpressing cells and mice [73-77].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [74]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, treatment of several AD Tg mice models with liver X receptor or retinoid X receptor agonists, which upregulate ApoE expression and enhance its lipidation status, resulted in reduction of Ab plaque load through enhancing clearance of Ab by glial cells.43,44”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [44]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recently, the RXR agonist bexarotene has been reported to facilitate the intracellular degradation of soluble A 1-42 in a PPAR␥-, liver X receptor-, and apolipoprotein E-dependent manner (Cramer et al., 2012).”
From PPARγ/RXRα-Induced and CD36-Mediated Microglial Amyloid-β Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice (2012) · cites this paper as Cramer et al., 2012
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“apoE is a central apolipoprotein in cerebral cholesterol metabolism and is involved in brain amyloid metabolism, blood brain barrier integrity, and transport of various lipid species to neuronal cells [15][16][17][18][19].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The similar findings presently observed for rare APOE variants with low apoE may reflect that the intracerebral vasculature, brain tissue and blood-brain barrier are dependent on normal levels of apoE for sufficient local lipid transport and βamyloid clearance [17,18,31,43].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Bexarotene is an FDA-approved liver X receptor/retinoid X receptor agonist for use in refractory cutaneous T cell lymphoma and has been shown to enhance Aβ clearance and improve cognitive performance in plaque-depositing mouse models209.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [209]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Still, recent findings that pharmacological induction of Apoe expression in mice ameliorates Aβ production and plaque deposition strongly supports an inverse correlation of APOE concentration with brain Aβ levels (Cramer et al., 2012).”
From The Pro-Neurotrophin Receptor Sortilin Is a Major Neuronal Apolipoprotein E Receptor for Catabolism of Amyloid-β Peptide in the Brain (2013) · cites this paper as Cramer et al., 2012
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“significantly reduces insoluble A after 3 days”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [76]
The cited source says what the claim attributes to it.
In the citing paper
“although plaque levels at 3 months remained unchanged (76).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [76]
The cited source says what the claim attributes to it.
In the citing paper
“decreases soluble A in mice within hours”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [76]
The cited source says what the claim attributes to it.
In the citing paper
“Cramer et al. demonstrated that RXR activation facilitate Aβ clearance in an ApoE dependent manner [74].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [74]
The cited source says what the claim attributes to it.
In the citing paper
“These published data indicate that the ApoE/Ab interaction may result in multidirectional effects that may promote Ab degradation by nonneuronal cells 43,44 while enhancing Ab accumulation in neurons.”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [44]
The cited source says what the claim attributes to it.
In the citing paper
“Recently, we have shown that activation of the Retinoid X Receptor, the obligate heterodimeric partner of PPARγ and LXRs, rapidly reverses AD pathology in mouse models of AD, and many of the beneficial effects seen in that study may occur through activation of PPAR signaling pathways (Cramer et al., 2012).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Cramer et al., 2012
The cited source says what the claim attributes to it.
In the citing paper
“In addition, several studies have demonstrated that increasing apoE lipidation, either through genetic or pharmacological approaches, promotes Aβ clearance and improves cognitive performance in mice (27, 44, 45).”
From APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [45]
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In the citing paper
“This should be seen in the context that b-amyloid markers do become abnormal up to 20 years before clinical symptoms become overt [114], and because expression of apoE in the brain mediates clearance of amyloid-b peptides [89], a clearance that is impaired in Alzheimer disease [90].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [89]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, induction of murine Apoe expression improves amyloid-b clearance and cognition; this finding also underlines the importance of the level of apoE [89].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [89]
The cited source says what the claim attributes to it.
In the citing paper
“the administration of RXR or LXR agonists reduces Aβ aggregation and restores cognitive function in AD mouse model (11, 12)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Bexarotene has shown therapeutic effects in AD model mice (11)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“In fact, increasing the levels and lipidation of apoE is a therapeutic mechanism attributed to the class of peroxisome proliferator-activated receptor-γ, retinoid × receptor, and liver × receptor agonists that have shown recent promise (Cao et al., 2007, Cramer et al., 2012, Lefterov et al., 2007, Terwel et al., 2011).”
From Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner (2014) · cites this paper as Cramer et al., 2012
The cited source says what the claim attributes to it.
In the citing paper
“In 2012, Cramer et al. elegantly demonstrated that oral administration of this molecule decreased the area and number of A plaques, increased the clearance of A peptides, stimulated memory (contextual fear conditioning) and olfactory functions, and improved the social behavior (construction nest) of treated AD mice [17].”
The cited source says what the claim attributes to it.
In the citing paper
“Bexarotene has been shown to induce the expression of ApoE in several CNS cell types and in brain extracts [17,63,64]”
In the citing paper
“Oral administration of the RXR agonist bexarotene in a mouse model of AD facilitated rapid clearance of soluble Aβ (103). The therapeutic effect was linked to the induction of increased levels of ApoE. Moreover, a recent study showed that bexarotene induces TREM2 expression in microglia (197).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [103]
In the citing paper
“Bexarotene has been reported to improve memory, cognition, and pathology in mouse models of AD819 and aging11 and is now in early phase clinical trials2021.”
From Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease (2017) · cites this paper as [8]
In the citing paper
“Bexarotene has previously been shown to reduce amyloid plaque pathology in APP/PS1, APPPS1–21, and Tg2576 mouse models of AD8.”
From Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease (2017) · cites this paper as [8]
In the citing paper
“Furthermore, bexarotene induces microglial and astrocyte-mediated clearance of A peptides, although the corresponding cellular and molecular mechanisms have yet to be characterized in detail [17].”
In the citing paper
“In 2012, Cramer et al. elegantly demonstrated that oral administration of this molecule decreased the area and number of A plaques, increased the clearance of A peptides, stimulated memory (contextual fear conditioning) and olfactory functions, and improved the social behavior (construction nest) of treated AD mice [17].”
In the citing paper
“In 2012, Cramer et al. elegantly demonstrated that oral administration of this molecule decreased the area and number of A plaques, increased the clearance of A peptides, stimulated memory (contextual fear conditioning) and olfactory functions, and improved the social behavior (construction nest) of treated AD mice [17].”
In the citing paper
“In 2012, Cramer et al. elegantly demonstrated that oral administration of this molecule decreased the area and number of A plaques, increased the clearance of A peptides, stimulated memory (contextual fear conditioning) and olfactory functions, and improved the social behavior (construction nest) of treated AD mice [17].”
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Metadata
- Authors
- Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y. D., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., Brunden, K. R., Wilson, D. A., & Landreth, G. E.
- Affiliations
- Case Western Reserve University (US)
- Washington University in St. Louis (US)
- Nathan Kline Institute for Psychiatric Research (US)
- University of Pennsylvania (US)
- Corresponding author
- Landreth, Gary E.
- ORCID
- Venue
- Science
- Published
- 2012-03-23
- Volume
- 335
- Issue
- 6075
- Pages
- 1503-1506
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3651582
- OpenAlex
- W2081388499
- Cited by
- 1,050
- References
- 31
- Citations by year
- 2026: 27 · 2025: 31 · 2024: 41 · 2023: 37 · 2022: 53 · 2021: 67 · 2020: 59 · 2019: 71 · 2018: 57 · 2017: 68 · 2016: 90 · 2015: 106 · 2014: 131 · 2013: 123 · 2012: 88
- FWCI
- 96.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG037693, AG030482-03S1, R01AG030482, K01AG029524, P50AG005681)
- National Institute on Deafness and Other Communication Disorders (DC-003906, R01DC003906)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta clearance, apolipoprotein E, bexarotene, retinoid X receptor, PPARγ, liver X receptor, nuclear receptor agonists, amyloid plaques, cognitive impairment, social dysfunction, olfactory dysfunction, neural circuit function
- MeSH terms
- Liver X Receptors, Bexarotene, Alzheimer Disease, Amyloidosis, Animals, Apolipoproteins E, Astrocytes, Behavior, Animal, Brain, Disease Models, Animal, Male, Mice, Inbred C57BL, Mice, Transgenic, Odorants, Olfactory Pathways, Phagocytosis, Tetrahydronaphthalenes, Amyloid beta-Peptides, Microglia, Extracellular Fluid, Retinoid X Receptors, PPAR gamma, Mice, Orphan Nuclear Receptors, Plaque, Amyloid, Molecular Targeted Therapy
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