Liver X receptor activation restores memory in aged AD mice without reducing amyloid

Vanmierlo, Tim; Rutten, Kris; Dederen, Jos; Bloks, Vincent W.; Zee, Leonie C. van Vark-van der; Kuipers, Folkert; Kiliaan, Amanda J.; Blokland, Arjan; Sijbrands, Eric J.G.; Steinbusch, Harry W.M.; Prickaerts, Jos; Lütjohann, Dieter; Mulder, Monique

doi:10.1016/j.neurobiolaging.2009.07.005

Cited by 125 publications

(126 citation statements)

References 56 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Jiang et al (2008) found a reduction in plaque-load in 16-month-old Tg2576 mice, but tested behavior in 5-month-old Tg2576 mice. In contrast, Vanmierlo et al (2009) did not find a reduction in plaque-load, but found a behavioral improvement in 23-monthold APPSLxPS1mut mice. In the present study, a reduction in plaque-load was observed in 13-month-old APP23 mice, but only a minor behavioral improvement.…”

Section: Behavioral Effects Of To901317 In Ad Modelsmentioning

confidence: 62%

“…The differences between these studies are likely to be found in differences in animal models, ages, dosage of compound, type of compound, and routes and duration of administration used. For example, in the study by Lefterov et al (2007) and in the present study, oral gavage of 50 mg/kg TO901317 per day was used, whereas Vanmierlo et al (2009) administered the compound in the food at a lower dose (30 mg/kg per day). Vanmierlo et al (2009) determined the optimal dose by short-term treatment regimens.…”

Section: Behavioral Effects Of To901317 In Ad Modelsmentioning

confidence: 99%

“…For example, in the study by Lefterov et al (2007) and in the present study, oral gavage of 50 mg/kg TO901317 per day was used, whereas Vanmierlo et al (2009) administered the compound in the food at a lower dose (30 mg/kg per day). Vanmierlo et al (2009) determined the optimal dose by short-term treatment regimens. However, Lefterov et al (2007) observed that drug effects wear off with time of treatment.…”

Section: Behavioral Effects Of To901317 In Ad Modelsmentioning

confidence: 99%

“…Short-term administration of LXR agonists TO901317 and GW3965 to 5-month-old preplaque Tg2576 mice improved fear conditioning (Riddell et al, 2007;Jiang et al, 2008) and longterm treatment with TO901317 restored object recognition in plaque-bearing APPSLxPS1mut mice (Vanmierlo et al, 2009). Long-term treatment with GW3965 has been shown to reduce plaque formation by 50% in aged Tg2576 mice ).…”

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Terwel¹,

Steffensen²,

Verghese³

et al. 2011

J. Neurosci.

163

115

View full text Add to dashboard Cite

Liver X receptors (LXRs) regulate immune cell function and cholesterol metabolism, both factors that are critically involved in Alzheimer's disease (AD). To investigate the therapeutic potential of long-term LXR activation in amyloid-␤ (A␤) peptide deposition in an AD model, 13-month-old, amyloid plaque-bearing APP23 mice were treated with the LXR agonist TO901317. Postmortem analysis demonstrated that TO901317 efficiently crossed the blood-brain barrier. Insoluble and soluble A␤ levels in the treated APP23 mice were reduced by 80% and 40%, respectively, compared with untreated animals. Amyloid precursor protein (APP) processing, however, was hardly changed by the compound, suggesting that the observed effects were instead mediated by A␤ disposal. Despite the profound effect on A␤ levels, spatial learning in the Morris water maze was only slightly improved by the treatment. ABCA1 (ATP-binding cassette transporter 1) and apolipoprotein E (ApoE) protein levels were increased and found to be primarily localized in astrocytes. Experiments using primary microglia demonstrated that medium derived from primary astrocytes exposed to TO901317 stimulated phagocytosis of fibrillar A␤. Conditioned medium from TO901317-treated ApoE Ϫ/Ϫ or LXR␣ Ϫ/Ϫ astrocytes did not increase phagocytosis of A␤. In APP23 mice, long-term treatment with TO901317 strongly increased the association of microglia and A␤ plaques. Short-term treatment of APP/PS1 mice with TO901317 also increased this association, which was dependent on the presence of LXR␣ and was accompanied by increased ApoE lipidation. Together, these data suggest that astrocytic LXR␣ activation and subsequent release of ApoE by astrocytes is critical for the ability of microglia to remove fibrillar A␤ in response to treatment with TO901317.

show abstract

Section: Behavioral Effects Of To901317 In Ad Modelsmentioning

confidence: 62%

Section: Behavioral Effects Of To901317 In Ad Modelsmentioning

confidence: 99%

Section: Behavioral Effects Of To901317 In Ad Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Terwel¹,

Steffensen²,

Verghese³

et al. 2011

J. Neurosci.

163

115

View full text Add to dashboard Cite

show abstract

“…Our study used exclusively female APP/PS1 mice, whereas APPSLxPS1mut males were used by Vanmielo et al (30) and Tg2576 males were used by Riddell et al (29). The gender of the Tg2576 cohort investigated by Jiang et al (13) is not reported.…”

Section: Discussionmentioning

confidence: 99%

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

Donkin

Stukas

Hirsch‐Reinshagen

et al. 2010

Journal of Biological Chemistry

171

148

View full text Add to dashboard Cite

The cholesterol transpoter ATP-binding cassette transporter A1 (ABCA1) moves lipids onto apolipoproteins including apolipoprotein E (apoE), which is the major cholesterol carrier in the brain and an established genetic risk factor for late-onset Alzheimer disease (AD). In amyloid mouse models of AD, ABCA1 deficiency exacerbates amyloidogenesis, whereas ABCA1 overexpression ameliorates amyloid load, suggesting a role for ABCA1 in A␤ metabolism. Agonists of liver X receptors (LXR), including GW3965, induce transcription of several genes including ABCA1 and apoE, and reduce A␤ levels and improve cognition in AD mice. However, the specific role of ABCA1 in mediating beneficial responses to LXR agonists in AD mice is unknown. We evaluated behavioral and neuropathogical outcomes in GW3965-treated female APP/PS1 mice with and without ABCA1. Treatment of APP/PS1 mice with GW3965 increased ABCA1 and apoE protein levels. ABCA1 was required to observe significantly elevated apoE levels in brain tissue and cerebrospinal fluid upon therapeutic (33 mg/kg/day) GW3965 treatment. At 33 mg/kg/day, GW3965 was also associated with a trend toward redistribution of A␤ to the carbonate-soluble pool independent of ABCA1. APP/PS1 mice treated with either 2.5 or 33 mg/kg/day of GW3965 showed a clear trend toward reduced amyloid burden in hippocampus and whole brain, whereas APP/ PS1-treated mice lacking ABCA1 failed to display reduced amyloid load in the whole brain and showed trends toward increased hippocampal amyloid. Treatment of APP/PS1 mice with either dose of GW3965 completely restored novel object recognition memory to wild-type levels, which required ABCA1. These results suggest that ABCA1 contributes to several beneficial effects of the LXR agonist GW3965 in APP/PS1 mice.Lipid metabolism is increasingly recognized to play a key role in the pathogenesis of Alzheimer disease (AD), 4 which is the leading cause of dementia in the elderly (1). AD is characterized by the presence of two neuropathological hallmarks including extracellular amyloid plaques that consist mainly of aggregated A␤ peptides and intracellular neurofibrillary tangles consisting of hyperphosphorylated Tau protein (2). Although the pathogenesis of AD is not completely understood, a leading hypothesis is that aberrant metabolism of A␤ peptides, which are derived by proteolytic cleavage from amyloid precursor protein (APP), triggers many of the toxic events in AD and eventually leads to both Tau and amyloid pathologies (3). Less than 5% of AD patients exhibit disease onset in their 40s and 50s due to genetic mutations that lead to increased production of A␤ peptides, particularly of the most detrimental A␤42 species (4). The cause of AD in more than 95% of subjects that typically develop AD in late life is unknown. As production of A␤ is generally not altered in these patients, age-related defects in A␤ degradation and clearance is emerging as a leading hypothesis for development of AD in the majority of patients (5).In mice, apoE exists in only one allelic state, ...

show abstract

Mitochondria‐associated endoplasmic reticulum membranes: At the crossroad between familiar and sporadic Alzheimer's disease

Wang

Zhang

2021

Synapse

View full text Add to dashboard Cite

Alzheimer's disease (AD), an incurable chronic neurodegenerative disease first described by Alois Alzheimer in 1906, has become a significant public health priority. After 10-15 years of preclinical stage, the symptoms develop from mild cognitive impairment to impaired memory, language difficulties and, at last, death in an average time of seven to ten years after diagnosis.After more than one hundred years of research, researchers had made tremendous progress. Nevertheless, Alzheimer's disease is still marked histologically by the accumulation of amyloid beta (Aβ), the emergence of neurofibrillary tangles, and loss of synapse. However, recently, with endless failure in clinical trials, some researchers are now turning to other symptoms such as aberrant lipid metabolism (Hamilton et al., 2015), abnormal calcium transfer (Dolev et al., 2013), and autophagic malfunction (Li et al., 2017). Mitochondria-associated endoplasmic reticulum membrane (MAM) is pivotal for the pathways mentioned above, which are disturbed in AD. Thus, Area-Gomez et al. proposed that disturbed MAM function is a "coherent and unified explanation" for both familial and sporadic AD: MAM hypothesis (Area-Gomez et al., 2012).In this review, we update the knowledge about MAM's role in pathologies shared by familial and sporadic forms of AD. We also highlight the importance of AD models used in studies.

show abstract

Liver X receptor activation restores memory in aged AD mice without reducing amyloid

Cited by 125 publications

References 56 publications

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

Mitochondria‐associated endoplasmic reticulum membranes: At the crossroad between familiar and sporadic Alzheimer's disease

Contact Info

Product

Resources

About