e7df2b604aafe206be57d398f4ccfc33 282476.pdf 8b86484df6f89b1e07a37d80a3cf14b4d7606947 282476.pdf 12f324d79d61224abcf5c69c73f32984c4324f7e6834e454e13a50bcad6e212c 282476.pdf Title: Hepatic Oxi-Inflammation and Neophobia as Potential Liver–Brain Axis Targets for Alzheimer’s Disease and Aging, with Strong Sensitivity to Sex, Isolation, and Obesity Subject: Research on Alzheimer’s disease (AD) has classically focused on alterations that occur in the brain and their intra- and extracellular neuropathological hallmarks. However, the oxi-inflammation hypothesis of aging may also play a role in neuroimmunoendocrine dysregulation and the disease’s pathophysiology, where the liver emerges as a target organ due to its implication in regulating metabolism and supporting the immune system. In the present work, we demonstrate organ (hepatomegaly), tissue (histopathological amyloidosis), and cellular oxidative stress (decreased glutathione peroxidase and increased glutathione reductase enzymatic activities) and inflammation (increased IL-6 and TNF) as hallmarks of hepatic dysfunction in 16-month-old male and female 3xTg-AD mice at advanced stages of the disease, and as compared to age- and sex-matched non-transgenic (NTg) counterparts. Moreover, liver–brain axis alterations were found through behavioral (increased neophobia) and HPA axis correlations that were enhanced under forced isolation. In all cases, sex (male) and isolation (naturalistic and forced) were determinants of worse hepatomegaly, oxidative stress, and inflammation progression. In addition, obesity in old male NTg mice was translated into a worse steatosis grade. Further research is underway determine whether these alterations could correlate with a worse disease prognosis and to establish potential integrative system targets for AD research. Keywords: Alzheimer’s disease; 3xTg-AD; liver–brain axis; obesity; HPA axis; corticosterone; oxidative stress; social isolation; amyloidosis; steatosis Author: Juan Fraile-Ramos, Anna Garrit, Josep Reig-Vilallonga and Lydia Giménez-Llort Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed May 31 08:39:21 2023 CEST ModDate: Wed May 31 08:45:36 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 20 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4238225 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HKBJPQ+VnURWPalladioL Type 1 Custom yes yes no 10 0 HHCMCU+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 SGLXMG+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 AEXFFA+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 DUJUUF+PazoMath-Italic Type 1 Builtin yes yes no 28 0 VVSYYB+EURM10 Type 1 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Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Animals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Extrinsic Factors: Naturalistic and Forced Social Isolation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Longitudinal Behavioral Assessment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Physical Status: Body Weight and Liver Index Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Histopathological Assessment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Children: Item: Title: Morphological and Structural Analysis with H&E Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Congo Red Staining for Amyloidosis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Biochemical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Children: Item: Title: HPA Axis: Glucocorticoids Measurements Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Hepatic Oxidative Stress Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Hepatic Inflammation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Functional Correlates Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Statistics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Children: Item: Title: Longitudinal Behavioral Assessment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Physical Status: Body Weight and Liver Index Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Histopathological Assessment: H&E and Congo Red Staining Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: Biochemical Status of the Liver Brain and HPA Axis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Meaningful Functional Correlates between Behavioral, Physical Metrics, Liver Oxidative Stress, and Inflammation Variables Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Children: Item: Title: Hepatic Pathology Changes according to Genotype Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Hepatic Oxi-Inflammation Metabolic Disruption Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: HPA Axis Disruption, Oxidative Stress, and Inflammation in the Liver Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: Meaningful Functional Correlates between Behavioral, Physical Metrics, Liver Oxidative Stress, and Inflammation Variables Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Info: Title: Hepatic Oxi-Inflammation and Neophobia as Potential Liver Brain Axis Targets for Alzheimer’s Disease and Aging, with Strong Sensitivity to Sex, Isolation, and Obesity Author: Juan Fraile-Ramos, Anna Garrit, Josep Reig-Vilallonga and Lydia Giménez-Llort Subject: Research on Alzheimer’s disease (AD) has classically focused on alterations that occur in the brain and their intra- and extracellular neuropathological hallmarks. However, the oxi-inflammation hypothesis of aging may also play a role in neuroimmunoendocrine dysregulation and the disease’s pathophysiology, where the liver emerges as a target organ due to its implication in regulating metabolism and supporting the immune system. In the present work, we demonstrate organ (hepatomegaly), tissue (histopathological amyloidosis), and cellular oxidative stress (decreased glutathione peroxidase and increased glutathione reductase enzymatic activities) and inflammation (increased IL-6 and TNF) as hallmarks of hepatic dysfunction in 16-month-old male and female 3xTg-AD mice at advanced stages of the disease, and as compared to age- and sex-matched non-transgenic (NTg) counterparts. Moreover, liver brain axis alterations were found through behavioral (increased neophobia) and HPA axis correlations that were enhanced under forced isolation. In all cases, sex (male) and isolation (naturalistic and forced) were determinants of worse hepatomegaly, oxidative stress, and inflammation progression. In addition, obesity in old male NTg mice was translated into a worse steatosis grade. Further research is underway determine whether these alterations could correlate with a worse disease prognosis and to establish potential integrative system targets for AD research. 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Annotation: Subtype: Link Rect: 102, 400, 138, 410 Annotation: Subtype: Link Rect: 477, 376, 515, 387 Annotation: Subtype: Link Rect: 521, 376, 557, 387 Annotation: Subtype: Link Rect: 59, 343, 96, 353 Annotation: Subtype: Link Rect: 102, 343, 138, 353 Annotation: Subtype: Link Rect: 131, 308, 168, 318 Annotation: Subtype: Link Rect: 478, 284, 515, 295 Annotation: Subtype: Link Rect: 521, 284, 557, 295 Annotation: Subtype: Link Rect: 451, 261, 489, 272 Annotation: Subtype: Link Rect: 95, 228, 133, 238 Annotation: Subtype: Link Rect: 108, 193, 146, 203 Annotation: Subtype: Link Rect: 113, 159, 150, 169 Annotation: Subtype: Link Rect: 113, 124, 150, 134 Annotation: Subtype: Link Rect: 99, 90, 137, 100 Annotation: Subtype: Link Rect: 143, 90, 179, 100 Annotation: Subtype: Link Rect: 152, 67, 190, 77 Annotation: Subtype: Link Rect: 196, 67, 232, 77 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 167, 710, 205, 721 Annotation: Subtype: Link Rect: 477, 687, 515, 698 Annotation: Subtype: Link Rect: 418, 664, 455, 675 Annotation: Subtype: Link Rect: 462, 664, 498, 675 Annotation: Subtype: Link Rect: 459, 641, 496, 652 Annotation: Subtype: Link Rect: 344, 606, 381, 617 Annotation: Subtype: Link Rect: 388, 606, 424, 617 Annotation: Subtype: Link Rect: 385, 583, 423, 594 Annotation: Subtype: Link Rect: 346, 560, 383, 571 Annotation: Subtype: Link Rect: 374, 538, 411, 548 Annotation: Subtype: Link Rect: 304, 514, 342, 525 Annotation: Subtype: Link Rect: 348, 514, 384, 525 Annotation: Subtype: Link Rect: 59, 492, 96, 502 Annotation: Subtype: Link Rect: 108, 469, 146, 479 Annotation: Subtype: Link Rect: 486, 445, 524, 456 Annotation: Subtype: Link Rect: 398, 435, 435, 445 Annotation: Subtype: Link Rect: 519, 411, 557, 422 Annotation: Subtype: Link Rect: 196, 389, 233, 399 Annotation: Subtype: Link Rect: 519, 365, 557, 376 Annotation: Subtype: Link Rect: 59, 354, 95, 364 Annotation: Subtype: Link Rect: 214, 330, 251, 341 Annotation: Subtype: Link Rect: 257, 330, 293, 341 Annotation: Subtype: Link Rect: 215, 307, 252, 318 Annotation: Subtype: Link Rect: 270, 284, 307, 295 Annotation: Subtype: Link Rect: 236, 261, 273, 272 Annotation: Subtype: Link Rect: 118, 228, 155, 238 Annotation: Subtype: Link Rect: 161, 228, 197, 238 Annotation: Subtype: Link Rect: 117, 205, 155, 215 Annotation: Subtype: Link Rect: 161, 205, 197, 215 Annotation: Subtype: Link Rect: 436, 192, 474, 203 Annotation: Subtype: Link Rect: 465, 169, 503, 180 Annotation: Subtype: Link Rect: 164, 136, 201, 146 Annotation: Subtype: Link Rect: 208, 136, 244, 146 Annotation: Subtype: Link Rect: 291, 112, 329, 123 Annotation: Subtype: Link Rect: 340, 78, 377, 88 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 451, 722, 488, 733 Annotation: Subtype: Link Rect: 495, 722, 531, 733 Annotation: Subtype: Link Rect: 214, 699, 251, 710 Annotation: Subtype: Link Rect: 257, 699, 293, 710 Annotation: Subtype: Link Rect: 160, 676, 197, 687 Annotation: Subtype: Link Rect: 203, 676, 239, 687 Annotation: Subtype: Link Rect: 419, 653, 456, 664 Annotation: Subtype: Link Rect: 113, 630, 150, 640 Annotation: Subtype: Link Rect: 156, 630, 192, 640 Annotation: Subtype: Link Rect: 375, 606, 412, 617 Annotation: Subtype: Link Rect: 419, 606, 455, 617 Annotation: Subtype: Link Rect: 113, 573, 150, 583 Annotation: Subtype: Link Rect: 292, 549, 329, 560 Annotation: Subtype: Link Rect: 335, 549, 371, 560 Annotation: Subtype: Link Rect: 59, 527, 96, 537 Annotation: Subtype: Link Rect: 113, 504, 151, 514 Annotation: Subtype: Link Rect: 157, 504, 193, 514 Annotation: Subtype: Link Rect: 418, 480, 456, 491 Annotation: Subtype: Link Rect: 398, 457, 436, 468 Annotation: Subtype: Link Rect: 338, 434, 376, 445 Annotation: Subtype: Link Rect: 59, 400, 96, 410 Annotation: Subtype: Link Rect: 59, 366, 96, 376 Annotation: Subtype: Link Rect: 102, 366, 138, 376 Annotation: Subtype: Link Rect: 358, 342, 396, 353 Annotation: Subtype: Link Rect: 194, 320, 232, 330 Annotation: Subtype: Link Rect: 238, 320, 274, 330 Annotation: Subtype: Link Rect: 310, 296, 348, 307 Annotation: Subtype: Link Rect: 413, 273, 451, 284 Annotation: Subtype: Link Rect: 457, 273, 493, 284 Annotation: Subtype: Link Rect: 445, 250, 482, 261 Annotation: Subtype: Link Rect: 159, 215, 197, 226 Annotation: Subtype: Link Rect: 203, 215, 239, 226 Annotation: Subtype: Link Rect: 59, 182, 96, 192 Annotation: Subtype: Link Rect: 102, 182, 138, 192 Annotation: Subtype: Link Rect: 451, 158, 488, 169 Annotation: Subtype: Link Rect: 495, 158, 531, 169 Checksum: a9639afa Type: CRC32 Checksum: e7df2b604aafe206be57d398f4ccfc33 Type: MD5 Checksum: 8b86484df6f89b1e07a37d80a3cf14b4d7606947 Type: SHA-1