12a5bf5b0fc19896e22906fa6071c08e 283633.pdf 0c9e18ae5412691ab8b92c6fa1ef90ddfd998139 283633.pdf d2d7459762ea08caf92cfcc27ddd8a2f7fa55b8f41ef15b38d887cd13603bd8e 283633.pdf Title: Survival Bias, Non-Lineal Behavioral and Cortico-Limbic Neuropathological Signatures in 3xTg-AD Mice for Alzheimer’s Disease from Premorbid to Advanced Stages and Compared to Normal Aging Subject: Pre-clinical research in aging is hampered by the scarcity of studies modeling its heterogeneity and complexity forged by pathophysiological conditions throughout the life cycle and under the sex perspective. In the case of Alzheimer’s disease, the leading cause of dementia in older adults, we recently described in female wildtype and APP23 mice a survival bias and non-linear chronology of behavioral signatures from middle age to long life. Here, we present a comprehensive and multidimensional (physical, cognitive, and neuropsychiatric-like symptoms) screening and underlying neuropathological signatures in male and female 3xTg-AD mice at 2, 4, 6, 12, and 16 months of age and compared to their non-transgenic counterparts with gold-standard C57BL/6J background. Most variables studied detected age-related differences, whereas the genotype factor was specific to horizontal and vertical activities, thigmotaxis, coping with stress strategies, working memory, and frailty index. A sex effect was predominantly observed in classical emotional variables and physical status. Sixteen-month-old mice exhibited non-linear age- and genotype-dependent behavioral signatures, with higher heterogeneity in females, and worsened in naturalistically isolated males, suggesting distinct compensatory mechanisms and survival bias. The underlying temporal and spatial progression of A and tau pathologies pointed to a relevant cortico-limbic substrate roadmap: premorbid intracellular A immunoreactivity and pSer202/pThr205 tau phosphorylation in the amygdala and ventral hippocampus, and the entorhinal cortex and ventral hippocampus as the areas most affected by A plaques. Therefore, depicting phenotypic signatures and neuropathological correlates can be critical to unveiling preventive/therapeutic research and intervention windows and studying adaptative behaviors and maladaptive responses relevant to psychopathology. Keywords: aging; Alzheimer’s disease; heterogeneity; cognitive deficits; neuropsychiatric-like symptoms; amygdala; ventral hippocampus; animal model; social isolation Author: Aida Muntsant, Maria del Mar Castillo-Ruiz and Lydia Giménez-Llort Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Sep 7 10:06:37 2023 CEST ModDate: Thu Sep 7 10:10:28 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 26 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 8306223 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MWHIBA+VnURWPalladioL Type 1 Custom yes yes no 10 0 CAMXTK+EURM10 Type 1 Builtin yes yes no 15 0 UDZHWT+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 PZXJXN+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 MDWXZE+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 BTFGED+VnURWPalladioL-Bold 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and Disrupt the Obsessive Compulsive Disorder-like Digging Ethogram Destination: subsection.2.2 Item: Title: Age-, Sex-, and Region-Dependent Accumulation of Intraneuronal A, Amyloid Plaques, and Aggregated Tau in 3xTg-AD Mice Destination: subsection.2.3 Item: Title: Discussion Destination: section.3 Children: Item: Title: Animal Models Are Invaluable Tools for Studying Mechanisms of AD Pathogenesis Destination: subsection.3.1 Item: Title: Age, Genotype, and Sex Modulation in Behavioral Signatures for Emotional, Cognitive, and Physical Phenotypes Destination: subsection.3.2 Item: Title: Effects of Social Housing Conditions on Behavioral Signatures Destination: subsection.3.3 Item: Title: Importance of Brain Regions Underlying Neuropsychiatric Symptoms in the 3xTg-AD Mouse Model Destination: subsection.3.4 Item: Title: Limitations Destination: subsection.3.5 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Animals Destination: subsection.4.1 Item: Title: Behavioral Assessments Destination: subsection.4.2 Children: Item: Title: Day 1: Corner and Open-Field Tests (CT and OF) Destination: subsubsection.4.2.1 Item: Title: Day 2: Recognition Tests (OF2 and OR) Destination: subsubsection.4.2.2 Item: Title: Day 3: Marble Test (MB) Destination: subsubsection.4.2.3 Item: Title: Days 4 and 5: Spontaneous Alternation and Working Memory Paradigm in the T-Maze (TM-SA and TM-WM) Destination: subsubsection.4.2.4 Item: Title: Days 6 to 10: Morris Water Maze (MWM) Destination: subsubsection.4.2.5 Item: Title: Physical Status: Body Weight (BW) and Mouse Clinical Frailty Index Assessment (FI) Destination: subsection.4.3 Item: Title: Brain Samples and Immunofluorescence Analysis Destination: subsection.4.4 Item: Title: Statistics Destination: subsection.4.5 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.6 Info: Title: Survival Bias, Non-Lineal Behavioral and Cortico-Limbic Neuropathological Signatures in 3xTg-AD Mice for Alzheimer’s Disease from Premorbid to Advanced Stages and Compared to Normal Aging Author: Aida Muntsant, Maria del Mar Castillo-Ruiz and Lydia Giménez-Llort Subject: Pre-clinical research in aging is hampered by the scarcity of studies modeling its heterogeneity and complexity forged by pathophysiological conditions throughout the life cycle and under the sex perspective. In the case of Alzheimer’s disease, the leading cause of dementia in older adults, we recently described in female wildtype and APP23 mice a survival bias and non-linear chronology of behavioral signatures from middle age to long life. Here, we present a comprehensive and multidimensional (physical, cognitive, and neuropsychiatric-like symptoms) screening and underlying neuropathological signatures in male and female 3xTg-AD mice at 2, 4, 6, 12, and 16 months of age and compared to their non-transgenic counterparts with gold-standard C57BL/6J background. Most variables studied detected age-related differences, whereas the genotype factor was specific to horizontal and vertical activities, thigmotaxis, coping with stress strategies, working memory, and frailty index. A sex effect was predominantly observed in classical emotional variables and physical status. Sixteen-month-old mice exhibited non-linear age- and genotype-dependent behavioral signatures, with higher heterogeneity in females, and worsened in naturalistically isolated males, suggesting distinct compensatory mechanisms and survival bias. The underlying temporal and spatial progression of A and tau pathologies pointed to a relevant cortico-limbic substrate roadmap: premorbid intracellular A immunoreactivity and pSer202/pThr205 tau phosphorylation in the amygdala and ventral hippocampus, and the entorhinal cortex and ventral hippocampus as the areas most affected by A plaques. Therefore, depicting phenotypic signatures and neuropathological correlates can be critical to unveiling preventive/therapeutic research and intervention windows and studying adaptative behaviors and maladaptive responses relevant to psychopathology. 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480, 371, 491 Annotation: Subtype: Link Rect: 377, 480, 413, 491 Annotation: Subtype: Link Rect: 131, 446, 168, 456 Annotation: Subtype: Link Rect: 131, 412, 168, 422 Annotation: Subtype: Link Rect: 180, 377, 217, 387 Annotation: Subtype: Link Rect: 512, 365, 550, 376 Annotation: Subtype: Link Rect: 163, 331, 201, 341 Annotation: Subtype: Link Rect: 59, 308, 96, 318 Annotation: Subtype: Link Rect: 227, 273, 264, 284 Annotation: Subtype: Link Rect: 270, 273, 306, 284 Annotation: Subtype: Link Rect: 478, 250, 515, 261 Annotation: Subtype: Link Rect: 521, 250, 557, 261 Annotation: Subtype: Link Rect: 160, 228, 198, 238 Annotation: Subtype: Link Rect: 204, 228, 240, 238 Annotation: Subtype: Link Rect: 392, 192, 429, 203 Annotation: Subtype: Link Rect: 436, 192, 472, 203 Annotation: Subtype: Link Rect: 197, 170, 235, 180 Annotation: Subtype: Link Rect: 496, 158, 533, 169 Annotation: Subtype: Link Rect: 268, 124, 305, 134 Annotation: Subtype: Link Rect: 59, 101, 96, 111 Annotation: Subtype: Link Rect: 362, 77, 399, 88 Page: Sequence: 25 Annotations: Annotation: Subtype: Link Rect: 156, 722, 194, 733 Annotation: Subtype: Link Rect: 303, 699, 340, 710 Annotation: Subtype: Link Rect: 347, 699, 383, 710 Annotation: Subtype: Link Rect: 319, 676, 357, 687 Annotation: Subtype: Link Rect: 363, 676, 399, 687 Annotation: Subtype: Link Rect: 519, 652, 557, 664 Annotation: Subtype: Link Rect: 59, 642, 95, 652 Annotation: Subtype: Link Rect: 161, 607, 199, 617 Annotation: Subtype: Link Rect: 205, 607, 241, 617 Annotation: Subtype: Link Rect: 470, 595, 508, 606 Annotation: Subtype: Link Rect: 371, 572, 408, 583 Annotation: Subtype: Link Rect: 127, 550, 164, 560 Annotation: Subtype: Link Rect: 156, 527, 193, 537 Annotation: Subtype: Link Rect: 202, 492, 240, 502 Annotation: Subtype: Link Rect: 131, 469, 168, 479 Annotation: Subtype: Link Rect: 422, 458, 460, 468 Annotation: Subtype: Link Rect: 466, 458, 502, 468 Annotation: Subtype: Link Rect: 519, 434, 557, 445 Annotation: Subtype: Link Rect: 59, 423, 95, 433 Annotation: Subtype: Link Rect: 293, 399, 331, 410 Annotation: Subtype: Link Rect: 337, 399, 373, 410 Annotation: Subtype: Link Rect: 59, 377, 96, 387 Annotation: Subtype: Link Rect: 102, 377, 138, 387 Annotation: Subtype: Link Rect: 449, 353, 486, 364 Annotation: Subtype: Link Rect: 493, 353, 529, 364 Annotation: Subtype: Link Rect: 156, 331, 193, 341 Annotation: Subtype: Link Rect: 348, 296, 386, 307 Annotation: Subtype: Link Rect: 412, 273, 449, 284 Annotation: Subtype: Link Rect: 452, 250, 489, 261 Annotation: Subtype: Link Rect: 519, 238, 556, 249 Annotation: Subtype: Link Rect: 455, 215, 492, 226 Annotation: Subtype: Link Rect: 498, 215, 534, 226 Annotation: Subtype: Link Rect: 150, 182, 188, 192 Annotation: Subtype: Link Rect: 194, 182, 230, 192 Annotation: Subtype: Link Rect: 258, 158, 296, 169 Annotation: Subtype: Link Rect: 302, 158, 338, 169 Annotation: Subtype: Link Rect: 109, 136, 146, 146 Annotation: Subtype: Link Rect: 248, 113, 285, 123 Annotation: Subtype: Link Rect: 310, 89, 347, 100 Annotation: Subtype: Link Rect: 497, 66, 534, 77 Page: Sequence: 26 Annotations: Annotation: Subtype: Link Rect: 131, 722, 168, 733 Annotation: Subtype: Link Rect: 464, 699, 502, 710 Annotation: Subtype: Link Rect: 131, 664, 168, 675 Annotation: Subtype: Link Rect: 458, 641, 496, 652 Annotation: Subtype: Link Rect: 502, 641, 538, 652 Annotation: Subtype: Link Rect: 386, 618, 423, 629 Annotation: Subtype: Link Rect: 346, 595, 383, 606 Annotation: Subtype: Link Rect: 389, 595, 425, 606 Annotation: Subtype: Link Rect: 423, 583, 461, 594 Annotation: Subtype: Link Rect: 467, 583, 503, 594 Annotation: Subtype: Link Rect: 418, 560, 456, 571 Annotation: Subtype: Link Rect: 462, 560, 498, 571 Annotation: Subtype: Link Rect: 204, 526, 242, 537 Annotation: Subtype: Link Rect: 385, 503, 423, 514 Checksum: 6daff069 Type: CRC32 Checksum: 12a5bf5b0fc19896e22906fa6071c08e Type: MD5 Checksum: 0c9e18ae5412691ab8b92c6fa1ef90ddfd998139 Type: SHA-1 Checksum: d2d7459762ea08caf92cfcc27ddd8a2f7fa55b8f41ef15b38d887cd13603bd8e Type: SHA-256