Knowing which and knowing what: a potential mouse model for age-related human declarative memory decline

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRβ-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-β (Aβ) deposition in an Alzheimer’s disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aβ and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aβ plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice independent of effects on Aβ load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline.

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Cellular Werner Phenotypes in Mice Expressing a Putative Dominant-Negative Human WRN Gene

Genetics ◽

10.1093/genetics/154.1.357 ◽

2000 ◽

Vol 154 (1) ◽

pp. 357-362

Author(s):

Lan Wang ◽

Charles E Ogburn ◽

Carol B Ware ◽

Warren C Ladiges ◽

Hagop Youssoufian ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mice ◽

Werner Syndrome ◽

Dominant Negative ◽

Dominant Negative Mutation ◽

Fibroblast Cultures ◽

Age Related

Abstract Mutations at the Werner helicase locus (WRN) are responsible for the Werner syndrome (WS). WS patients prematurely develop an aged appearance and various age-related disorders. We have generated transgenic mice expressing human WRN with a putative dominant-negative mutation (K577M-WRN). Primary tail fibroblast cultures from K577M-WRN mice showed three characteristics of WS cells: hypersensitivity to 4-nitroquinoline-1-oxide (4NQO), reduced replicative potential, and reduced expression of the endogenous WRN protein. These data suggest that K577M-WRN mice may provide a novel mouse model for the WS.

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Early-life chronic di(2-ethylhexyl)phthalate exposure worsens age-related long-term associative memory decline associated with insulin/IGF-1 signaling and CRH-1/CREB in Caenorhabditis elegans

Journal of Hazardous Materials ◽

10.1016/j.jhazmat.2021.126044 ◽

2021 ◽

pp. 126044

Author(s):

Chun Ming How ◽

Ting-An Lin ◽

Vivian Hsiu-Chuan Liao

Keyword(s):

Caenorhabditis Elegans ◽

Associative Memory ◽

Early Life ◽

Memory Decline ◽

Phthalate Exposure ◽

Age Related ◽

Ethylhexyl Phthalate

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Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3

Biology ◽

10.3390/biology10070622 ◽

2021 ◽

Vol 10 (7) ◽

pp. 622

Author(s):

Iswariyaraja Sridevi Gurubaran ◽

Hanna Heloterä ◽

Stephen Marry ◽

Ali Koskela ◽

Juha M. T. Hyttinen ◽

...

Keyword(s):

Oxidative Stress ◽

Mouse Model ◽

Macular Degeneration ◽

Complement Component ◽

Factor H ◽

Age Related Macular Degeneration ◽

Related Factor ◽

Complement Factor ◽

Age Related ◽

Dry Amd

Aging-associated chronic oxidative stress and inflammation are known to be involved in various diseases, e.g., age-related macular degeneration (AMD). Previously, we reported the presence of dry AMD-like signs, such as elevated oxidative stress, dysfunctional mitophagy and the accumulation of detrimental oxidized materials in the retinal pigment epithelial (RPE) cells of nuclear factor erythroid 2-related factor 2, and a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (NFE2L2/PGC1α) double knockout (dKO) mouse model. Here, we investigated the dynamics of inflammatory markers in one-year-old NFE2L2/PGC1α dKO mice. Immunohistochemical analysis revealed an increase in levels of Toll-like receptors 3 and 9, while those of NOD-like receptor 3 were decreased in NFE2L2/PGC1α dKO retinal specimens as compared to wild type animals. Further analysis showed a trend towards an increase in complement component C5a independent of component C3, observed to be tightly regulated by complement factor H. Interestingly, we found that thrombin, a serine protease enzyme, was involved in enhancing the terminal pathway producing C5a, independent of C3. We also detected an increase in primary acute phase C-reactive protein and receptor for advanced glycation end products in NFE2L2/PGC1α dKO retina. Our main data show C5 and thrombin upregulation together with decreased C3 levels in this dry AMD-like model. In general, the retina strives to mount an orchestrated inflammatory response while attempting to maintain tissue homeostasis and resolve inflammation.

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