Fornix volumetric increase and microglia morphology contribute to spatial and recognition-like memory decline in ageing male mice

Cárdenas-Tueme, Marcela; Trujillo-Villarreal, Luis A; Ramírez‐Amaya, Víctor; Garza‐Villarreal, Eduardo A.; Camacho‐Morales, Alberto; Reséndez‐Pérez, Diana

doi:10.1016/j.neuroimage.2022.119039

Cited by 4 publications

(3 citation statements)

References 51 publications

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“…In treated animals, mass spectrometry confirmed that 3TC crossed the blood–brain barrier (Figure 1c ), similar to what others have reported in pre‐clinical models (Wu et al, 1998 ), and we observed strong effects of 3TC on cognitive function when we measured spatial memory acquisition and short‐term recognition memory via the Barnes Maze and Novel Object Recognition tests, respectively. Consistent with other reports (Cárdenas‐Tueme et al, 2022 ), in the Barnes Maze, older control mice were slower to find the escape hole over time/repeated trials versus young controls. In contrast, older 3TC‐treated mice performed similarly to younger mice (Figure 1d ).…”

Section: Resultssupporting

confidence: 91%

The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction

et al. 2023

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Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age‐related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease. However, the effects of 3TC on cognitive function with aging have not been investigated. Here, in support of a role for TE transcripts in brain aging/cognitive decline, we show that 3TC: (a) improves cognitive function and reduces neuroinflammation in old wild‐type mice; (b) preserves neuronal health with aging in mice and Caenorhabditis elegans; and (c) enhances cognitive function in a mouse model of tauopathy. We also provide insight on potential underlying mechanisms, as well as evidence of translational relevance for these observations by showing that TE transcripts accumulate with brain aging in humans, and that these age‐related increases intersect with those observed in Alzheimer's disease. Collectively, our results suggest that TE transcript accumulation during aging may contribute to cognitive decline and neurodegeneration, and that targeting these events with reverse transcriptase inhibitors like 3TC could be a viable therapeutic strategy.

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Section: Resultssupporting

confidence: 91%

The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction

et al. 2023

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“…After behavioral phenotyping, the F1, F2 and F3 rats at postnatal day 72 were intraperitoneally anesthetized with an overdose of 1 ml of pentobarbital (PiSA Agropecuaria) and transcardially perfused following standardized methods as reported ( Trujillo-Villarreal et al, 2021 ; Cárdenas-Tueme et al, 2022 ; Maldonado-Ruiz et al, 2022 ). For MRI acquisition, the skulls were submerged and fixed inside plastic tubes filled with Fomblin (Sigma 317950-100G), and imaging was performed in a 16-cm-bore 7T Bruker PharmaScan MRI scanner using a 2 × 2 array surface rat head coil, interfaced to a Paravision 6.0.1 and 7.0.1 console (Bruker) with an inner diameter of 72 mm.…”

Section: Methodsmentioning

confidence: 99%

Paternal Prenatal and Lactation Exposure to a High-Calorie Diet Shapes Transgenerational Brain Macro- and Microstructure Defects, Impacting Anxiety-Like Behavior in Male Offspring Rats

Trujillo-Villarreal,

Cruz-Carrillo,

Angeles-Valdez

et al. 2024

eNeuro

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Prenatal exposure to high-energy diets (HED) increases the susceptibility for behavioral alterations in the male offspring. We addressed whether prenatal HED primes the transgenerational inheritance of structural brain changes impacting anxiety/depression-like behavior in the offspring. For this, we used female Wistar rats exposed to a HED (cafeteria diet, CAF, n = 6) or chow (control, CON, n= 6) during development. Anxiety and depression-like behavior was evaluated in the filial 1 (F1), filial 2 (F2) and filial 3 (F3) male offspring using the open field (OFT), elevated plus maze (EM), novelty suppressed feeding (NSFT), tail suspension (TST) and forced swimming (FST) tests. Structural brain changes were identified by deformation-based morphometry (DBM) and diffusion tensor imaging (DTI) usingex vivomagnetic resonance imaging (MRI). We found that the F1, F2 and F3 offspring exposed to CAF diet displayed higher anxious scores including longer feeding latency during the NSFT, and in the closed arms and only F1 offspring showed longer stay on edges during the OFT versus control offspring. DBM analysis revealed that CAF offspring exhibited altered volume in cerebellum, hypothalamus, amygdala and hippocampus preserved up to the F3 generation of anxious individuals. Also, F3 CAF anxious exhibited greater fractional anisotropy and axial diffusivity in the amygdala, greater apparent diffusion coefficient in the corpus callosum and greater axial diffusivity in the hippocampus respect to the control. Our results suggest that prenatal and lactation exposure to HED programs the transgenerationally inheritance of structural brain changes related to an anxiety-like behavior in the male offspring.Significance statementPrenatal and lactation programming by HED exposure primes the transgenerational inheritance of aberrant behaviors in the offspring. A deeper understanding of the effect of diet on structural brain alterations that code for anxiety-like behavior and their transgenerational inheritance may allow the identification of new targets for future interventions. We used magnetic resonance imaging to globally and selectively characterize diet-dependent structural brain changes and anxiety-like behavior in the F1, F2 and F3 generations of rats. The current findings suggest that prenatal and lactation exposure to HED affects brain structure leading to anxiety-like behavior which is transgenerational preserved on the F2 and F3 generations.

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“…Shahidehpour et al [ 30 ] performed a series of autopsies and found the increased levels of dystrophic microglia in the aged brain, which were also more common in older brains with neurodegenerative diseases, suggesting that dystrophic microglia are associated with neurodegenerative diseases rather than healthy aging. However, Cárdenas-Tueme et al [ 32 ] , using C57BL/6 male mice at 2, 12, and 20 months, found that the aging led to an increasing proportion of dystrophic microglia in the left medial entorhinal cortex, which resembled a "surveillance state" characterized by the extended processes capable of contacting cells and structures; at the same time, the aged male mice appeared to have a decreasing number of hypertrophic microglia in the fornix, accompanied by damage-associated molecular patterns featured with the downregulation of several microglial subtypes; in addition, based on further biological modeling, they also found that the age-related increases in the fornix volume were associated with dystrophic microglia, thereby contributing to cognitive decline. Taken together, the morphological changes caused by aging are not absolute, and hypertrophic microglia and dystrophic microglia can both exist in an aging brain.…”

Section: Microglia In Healthy Brain Agingmentioning

confidence: 99%

Microglia in brain aging: An overview of recent basic science and clinical research developments

Fan¹,

Zhang²,

Wen³

et al. 2024

J Biomed Res

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Aging is characterized by progressive degeneration of tissues and organs, and it is positively associated with an increased mortality rate. The brain, as one of the most significantly affected organs, experiences age-related changes, including abnormal neuronal activity, dysfunctional calcium homeostasis, dysregulated mitochondrial function, and increased levels of reactive oxygen species. These changes collectively contribute to cognitive deterioration. Aging is also a key risk factor for neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. For many years, neurodegenerative disease investigations have primarily focused on neurons, with less attention given to microglial cells. However, recently, microglial homeostasis has emerged as an important mediator in neurological disease pathogenesis. Here, we provide an overview of brain aging from the perspective of the microglia. In doing so, we present the current knowledge on the correlation between brain aging and the microglia, summarize recent progress of investigations about the microglia in normal aging, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and then discuss the correlation between the senescent microglia and the brain, which will culminate with a presentation of the molecular complexity involved in the microglia in brain aging with suggestions for healthy aging.

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Fornix volumetric increase and microglia morphology contribute to spatial and recognition-like memory decline in ageing male mice

Cited by 4 publications

References 51 publications

The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction

The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction

Paternal Prenatal and Lactation Exposure to a High-Calorie Diet Shapes Transgenerational Brain Macro- and Microstructure Defects, Impacting Anxiety-Like Behavior in Male Offspring Rats

Microglia in brain aging: An overview of recent basic science and clinical research developments

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