Photobiomodulation (PBM) therapy, using low intensity near-infrared light is a noninvasive form of treatment with no side effects can be used to treat Alzheimer’s disease (AD). In a double-transgenic mouse model of AD (APPswe/PS1dE9), chronic PBM therapy has been shown to reduce Aβ plaques accumulation in specific regions of the brain, including the neocortex and hippocampus. The aim of this study was to analyze the effects of PBM therapy on brain cortex neuroprotective gene expression and behavior in this APPswe/PS1dE9 mouse model. Six-month old male AD (AD-PBM, n = 7) and wild type litter mate mice (WT-PBM, n = 8) were exposed to near-infrared light (wavelength 850 nm, 4.5 J/cm2, 3min/day, 5 days/week) for 6 months. Control mice (AD-CNT, n = 7; WT-CNT, n = 7) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Motor function was assessed with treadmill-based gait analysis, with metrics including hind propel, hind stance and hind step angle (DigiGait), and open field test (OFT; anxiety-like behavior) following 6 months of treatment. Gene expression sampled from cortex was analyzed by qPCR. Data were analyzed by 2-way ANOVA. In the AD group, PBM therapy significantly increased the expression of neuroprotective genes TGFb1, INFG, EGFR and MMP2, but did not affect the expression of these genes in WT (Fig. 1A-D). In the gait analysis, PBM groups significantly reduced hind step angle in AD, but not WT (Fig. 1E). In the OFT, genotype had a significant effect on the amount of distance and time spent in the center of the arena (Table); non-treated WT mice exhibited lower anxiety level vs. non-treated AD mice (Fig. 1F). PBM did not have a significant effect, but the percent of distance spent in the center out of total distance had an increasing trend (Fig. 1F) indicating a trend in a reduction of anxiety in the AD group. Two-way ANOVA analysis results are presented in Table 1. PBM therapy significantly increased neuroprotective cortical gene expression and improved motor function in AD mice. It is possible that PBM treatment contributes to the upregulation of neuroprotective genes that reduced anxiety behavior and improved motor function.

Early vascular aging (EVA), manifesting as increases in central arterial stiffness and BP, is associated with cognitive impairment in humans. EVA and cognitive impairment occurs in Dahl salt-sensitive (DSS) rats consuming a normal salt (NS) diet with an advancing age. Quercetin (QRC), a flavonoid with anti-oxidant, anti-inflammatory and senolytic properties, previously shown to reduce salt-sensitive hypertension in DSS. We hypothesized that QRC will not only reduce EVA but will also improve cognitive function in DSS consuming NS diet. Six month old male DSS rats were assigned to two groups: a control group (n = 12) on a normal salt diet (0.5% NaCl) and an experimental group (n = 24) receiving the same diet supplemented with QRC (100 mg/kg BW/daily) for a 3-month period. Systolic and diastolic blood pressure (SBP, DBP), pulse wave velocity (PWV, an index of CAS), echocardiography, and visuospatial attention test were assessed before and after QRC treatment or placebo. Before treatment, no differences existed between groups. From 6 to 9 months of age in the control group, SBP, DBP, and PWV increased, while heart rate (HR) and ejection fraction (EF) showed a borderline decrease, and attention behavior showed a borderline increase for 1.0s of stimulus duration and no change for shorter visual stimulus, 0.2s (Figure and Table). QRC treatment reduced SBP, PWV, and increased EF and attention. The QRC effect was to increase the number of correct responses for 0.2s of stimulus and was negatively correlated with PWV (Pearson r = -0.420, P = 0.02) but not with BP, indicating that CAS is linked to cognitive function. QRC supplementation demonstrated the ability to reduce EVA and enhance cognition in DSS rats, as indicated by attention behavior. Despite BP and CAS reflecting EVA, the association between attention decline and PWV, but not BP, implies that CAS is linked to cognitive function through mechanisms not directly related to BP. Further exploration is required to understand the mechanistic basis of QRC effects on EVA in DSS rats. Supported by NIA/NIH/IRP

The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. TOP3B mutations in humans are associated with schizophrenia, autism and cognitive disorders; and Top3b-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we generated a Tdrd3-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to Top3b-null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to Tdrd3-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive and psychiatric disorders.

Objective: Quercetin (QRC), a flavonoid with anti-oxidant, anti-inflammatory and senolytic effects, reduced BP in salt-induced hypertension in Dahl salt-sensitive (DSS) rats. The increases in central arterial stiffness (CAS) and blood pressure (BP) occur, as manifestation of early vascular aging (EVA), in DSS rats even consuming a normal salt (NS) diet, moreover, EVA is associated with cognitive impairment in humans. We hypothesized that as age advances, a decline in cognitive function will accompany EVA in DSS rats consuming a NS diet, and that QRC will not only retard EVA, but also will improve cognitive function. Design and method: A NS diet (0.5% NaCl), supplemented with QRC (100 mg/kg BW/day) was administered to male DSS rats at 6-mo of age (n=24) for a 3-month period. DSS without QRC supplementation served as a control group (n=12). Systolic and diastolic BP (SBP, DBP), pulse wave velocity (PWV, an index of CAS), echocardiography, and a visuospatial attention test were assessed prior to and following QRC treatment. Results: At 6-mo of age none of the measured parameters differ between control and QRC rats. During aging from 6- to 9-mo in the control group, SBP, DBP and PWV significantly increased, ESLV.vol showed a statistically borderline trend to increase, HR and EF showed a statistically borderline trend to decrease, and attention behavior did not change. QRC treatment reduced SBP, PWV, and ESLV.vol, and increased EF and attention (Table). The QRC effect to increase the number of correct attention test responses was inversely correlated with PWV (Pearson r=-0.420, P=0.02) but not with BP or cardiac parameters, indicating that CAS but not BP is linked to cognitive function. Conclusions: QRC reduces EVA and improves cognition assessed as an attention behavior. Although both BP and CAS are manifestations of EVA, a positive association between attention decline with PWV, but not BP, suggests that CAS is linked to cognitive function via mechanisms that are not directly related to BP. Further studies are required to determine whether the effects of QRC on EVA in DSS rats, consuming a NS diet, are linked to its anti-oxidant, anti-inflammatory or senolytic properties.

Abstract Comprehending aging’s molecular mechanisms, like RNA splicing and AMPK signaling, is vital for tackling age-related issues and boosting resilience. Oxygen fluctuations from obstructive sleep apnea (OSA) cause Intermittent Hypoxia (IH), affecting respiratory functions and health, prompting adaptive responses to counter reduced energy production. Mice as models allow simulating disorders and studying muscle cell protection under low oxygen levels. Over the past two years, we have collected more than 1500 samples from 15 different tissues of adult (9-11 months) and old (20-23 months) mice exposed to IH at 21% to 5% oxygen concentration in 2:30 minutes cycles, for 8 hours a day over 4-8 weeks, aiming to construct a comprehensive murine IH atlas by employing cutting-edge technologies across diverse tissues. Analyses include conducting detailed transcriptomic analyses of muscle tissues using hybrid RNA-seq to identify changes in splicing isoforms during IH experiments, exploring transitions between fast-to-slow fiber types, studying mitochondrial morphology using C57/BL6 and mtKeima mouse strains (both wild-type and Alzheimer’s disease models), investigating brain spatial transcriptomics to understand the neurological effects of IH, analyzing cardiorespiratory disruptions by examining the epigenetic clock of the heart and spleen, and delving into the role of liver extracellular vesicles (EVs), particularly exosomes, in our sensitive mouse IH model. The overarching goal of this project is to integrate omics data comprehensively to elucidate the impact of alternate hypoxia on health and aging and develop innovative therapeutic strategies that minimize damage in patients affected by this highly prevalent conditions in older persons.

Alzheimer’s disease (AD) is linked to toxic Aβ plaques in the brain and activation of innate responses. Recent findings however suggest that the disease may also depend on the adaptive immunity, as B cells exacerbate and CD8+ T cells limit AD-like pathology in mouse models of amyloidosis. Here, by artificially blocking or augmenting CD8+ T cells in the brain of 5xFAD mice, we provide evidence that AD-like pathology is promoted by pathogenic, proinflammatory cytokines and exhaustion markers expressing CXCR6+ CD39+CD73+/- CD8+ TRM-like cells. The CD8+ T cells appear to act by targeting disease associated microglia (DAM), as we find them in tight complexes with microglia around Aβ plaques in the brain of mice and humans with AD. We also report that these CD8+ T cells are induced by B cells in the periphery, further underscoring the pathogenic importance of the adaptive immunity in AD. We propose that CD8+ T cells and B cells should be considered as therapeutic targets for control of AD, as their ablation at the onset of AD is sufficient to decrease CD8+ T cells in the brain and block the amyloidosis-linked neurodegeneration.

Olfactory dysfunction is a prevalent symptom and an early marker of age-related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's Diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age-related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice. Our results showed that selective loss of odor discrimination was the earliest smelling behavioral change with aging, followed by a decline in odor sensitivity and detection while odor habituation remained in old mice. Compared to behavioral changes related with cognitive and motor functions, smelling loss was among the earliest biomarkers of aging. During aging, metabolites related with oxidative stress, osmolytes, and infection became dysregulated in the olfactory bulb, and G protein coupled receptor-related signaling was significantly down regulated in olfactory bulbs of aged mice. Poly ADP-ribosylation levels, protein expression of DNA damage markers, and inflammation increased significantly in the olfactory bulb of older mice. Lower NAD+ levels were also detected. Supplementation of NAD+ through NR in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health.

Alzheimer’s disease (AD) is characterized by brain amyloid-β plaque formation, neuroinflammation and neurodegeneration, which lead to cognitive impairment (CI) and disruption of circadian rhythm. Bioactive steroidal Na/K-ATPase inhibitor marinobufagenin (MBG) modulates neuroinflammation. In 16-mo old double transgenic APPswe/PS1dE9 AD mice with advanced AD, treatment with MBG reduced mRNA expression of inflammatory markers. Here, we investigated whether treatment with MBG at early-stage AD may impact AD manifestation in this AD mouse model. Five months old male AD mice (n = 15) and WT mice (n = 28) were administered MBG (100 µg/day/kg body weight) (AD-MBG, n = 8; WT-MBG, n = 14) or vehicle for control (AD-C, n = 7; WT-C, n = 14) via subcutaneous ALZET osmotic minipumps for 3 months. At 8-mo of age, the mice underwent turn-based discrimination learning in a water T-maze (WTM) to assess procedural learning and 72-hour home cage activity (HCA) analysis to assess circadian rhythm. The hippocampal inflammatory and AD mRNAs (by qPCR) and MBG levels (by immunoassay) were measured. MBG administration increased plasma MBG levels in WT and AD mice (Table 1). AD-C mice exhibited greater home cage activity disruption vs. WT-C (Fig.1a); in WTM, AD-C required more trials to learn the turn-based task than WT-C (Fig. 1b). Though statistically insignificant, trends showed that MBG numerically worsened activity disruption by HCA and decreased ability to learn turn-based task by WTM in WT mice, while numerically improving both measures in AD mice. During the reversal phase of WTM where response requirements were reversed, WT-C mice performed significantly better than AD-C mice, measured by the cumulative amount of time spent in the incorrect arm until reaching criterion performance (p = 0.038). Similar patterns of numerical improvement in AD-MBG compared to AD-C are shown (Fig. 1c). Hippocampal inflammatory and AD markers mRNAs were upregulated in AD-C vs. WT-C, and MBG treatment downregulated the expression of TNF and GFAP in AD mice (Table 1). Behavioral testing results illustrate CI and circadian impairment in 8-mo old AD mice compared to WT. Numerical trends show a potential protective effect of MBG on AD CI likely via downregulation of hippocampal TNF and GFAP genes. 0Supported by the NIH/NIA Intramural Research Program

Cardiovascular diseases (CVD), including increased central arterial stiffness (CAS), accompany chronic kidney disease (CKD) development. An increase in pulse wave velocity (PWV), an index for CAS, is implicated in age-associated changes in the brain and potentiates the development of CI in CVD and CKD in humans and animal models. The aim of this study was to determine whether inducing CKD accelerates the development of CI and CAS in aged male and female rats. Ten months-old male and female Sprague-Dawley rats were fed with 0.25% adenine diet to accelerate CKD (n = 10-12; CKD-male, CKD-female) or regular diet (n = 8-10; CNT-male, CNT-female) for 8weeks. Body weight (BW), blood pressure (BP), heart rate (HR), aortic-PWV (aPWV), behavioral tests, blood urea nitrogen (BUN), creatinine and hematocrit were assessed at the endpoint. The anxiety-like behavior was tested in open field test (OFT) and elevated plus maze (EPM). Morris water maze (MWM) and cross maze (CM) were used to test spatial memory. The data were analyzed using two-way ANOVA. CKD development in both sexes was accompanied by kidneys enlargement, increase in BUN and creatinine, and reduction in hematocrit. In CKD-male the kidney function was more compromised with higher levels of BUN and creatinine vs. CKD-female (Table 1). CKD-male had lower BW and SBP vs. CNT-male (Table 1). CKD induced a reduction in HR, increase in aPWV and aortic weight in both sexes vs. respective CNT-groups (Figure 1). Both CKD-male and CKD-female demonstrated a tendency of increase in path length to find the hidden platform in MWM, e.g., both sexes had numerically impaired spatial memory. CKD-male spent less time in the center of OFT, a measure of anxiety, and loss of spatial memory, with a reduction of spontaneous alternation task assessed by CM. CKD-female exhibited higher level of anxiety spending less time in open arm of EPM vs. CNT-female (Figure 2). CKD development in old male and female Sprague-Dawley rats was accompanied by an increase in CAS, cardiovascular remodeling, and cognitive dysfunction. In CKD, CI affected different cognitive domains in the old males than in the age-matched females. Supported by NIA/NIH/IRP

BACKGROUND The central nervous system's influence on cardiac function is well described; however, direct evidence for signaling from heart to brain remains sparse. Mice with cardiac-selective overexpression of adenylyl cyclase type 8 (TGAC8) display elevated heart rate/contractility and altered neuroautonomic surveillance.OBJECTIVES In this study the authors tested whether elevated adenylyl cyclase type 8-dependent signaling at the cardiac cell level affects brain activity and behavior.METHODS A telemetry system was used to record electrocardiogram (ECG) and electroencephalogram (EEG) in TGAC8 and wild-type mice simultaneously. The Granger causality statistical approach evaluated variations in the ECG/EEG relationship. Mouse behavior was assessed via elevated plus maze, open field, light-dark box, and fear conditioning tests. Transcriptomic and proteomic analyses were performed on brain tissue lysates.RESULTS Behavioral testing revealed increased locomotor activity in TGAC8 that included a greater total distance traveled (+43%; P < 0.01), a higher average speed (+38%; P < 0.01), and a reduced freezing time (-45%; P < 0.01). Dual-lead telemetry recording confirmed a persistent heart rate elevation with a corresponding reduction in ECG-R waves interval variability and revealed increased EEG-gamma activity in TGAC8 vs wild-type. Bioinformatic assessment of hippocampal tissue indicated upregulation of dopamine 5, gamma-aminobutyric acid A, and metabotropic glutamate 1/5 receptors, major players in gamma activity generation. Granger causality analyses of ECG and EEG recordings showed a marked increase in informational flow between the TGAC8 heart and brain.CONCLUSIONS Perturbed signals arising from the heart cause changes in brain activity, altering mouse behavior. More specifically, the brain interprets augmented myocardial humoral/functional output as a "sustained exercise-like" situation and responds by activating central nervous system output controlling locomotion.

Photobiological modulation (PBM) therapy, a form of low-dose light therapy, is beneficial in treating various disease conditions including Alzheimer’s disease (AD). Double-transgenic mice (APPswe/PS1dE9) develop progressive accumulation of amyloid-β (Aβ) plaques, cognitive impairment, and alterations in cardiovascular structure and function, and represent a model of AD. Prior studies have shown that PBM therapy reduces the size and number of Aβ plaques in the neocortex and hippocampus in the mouse models of AD. The aim of this study was to investigate the effects of PBM on cardiovascular structure and function and cognitive function in the aged AD mice. Six-month old female AD (APPswe/PS1dE9; AD-PBM, n = 8) and wild type mice (WT-PBM, n = 8) were exposed to near-infrared light (wavelength 850 nm, 4.5 J/cm 2 , 3min/day, 5 days/week) for 6 months. Control mice (AD-CNT, n = 6; WT-CNT, n = 6) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Cardiac parameters were measured by echocardiography. Gait analysis (DigiGait), home cage activity (HCA), and spatial working memory (indicated by alternation rate in cross maze test, CM) were assessed after 6 months of treatment. Group differences were identified by two-way ANOVA. In HCA test, the AD-CNT mice exhibited circadian locomotor hyperactivity at night-time relative to WT-CNT mice (Figure 1A, B), which was reduced by PBM. AD-CNT mice had lower alternation rates in CM, indicating spatial working memory impairment. PBM had minimal effect on this parameter (Table 1). The AD-CNT vs. WT-CNT mice manifested differences in several gait parameters, specifically, they demonstrated a lower fore propel time than WT-CNT. PBM normalized this parameter in AD-PBM mice to the level of WT-CNT (Figure 1C). Both WT-PBM and AD-PBM mice had improved cardiovascular structure, which was demonstrated by lower relative wall thickness of left ventricle (LV) and LV mass, and higher LV volume at the end of diastole in PBM-treated vs. correspondent CNT groups (Table 1, Figure 2). PBM improved cardiovascular structure and AD-associated cognitive impairment in the APP/PS1 mouse model. It is possible that more effective cardiovascular structure and function contributes to Aβ removal from the brain after PBM treatment. Supported by NIA/NIH/IRP

Introduction: Blood pressure (BP) begins to increase early in life in Dahl salt-sensitive rats (DSS) that consume a normal salt (NS) diet. Epidemiologic studies have shown that early vascular aging (EVA) is associated with central arterial stiffening (CAS) and hypertension, which develop earlier in life than expected in general population and contribute to cognitive impairment later in life. Hypotheses: (i) DSS rats will develop EVA earlier in life on NS diet, and with advancing age will exhibit early CV aging; (ii) In DSS, CV remodeling and CAS are implicated in memory decline. We tested these hypotheses using a longitudinal repeated measure design in DSS and their parental breed Sprague-Dawley rats (SD) at 3- & 12-mo of age. Methods: Male SD and DSS were kept on NS diet (0.5% NaCl; n=8/group) for entire experiment. Repeated measures of systolic BP (SBP), pulse wave velocity (PWV; an index of CAS), echocardiography, and non-repeated measures of Morris water maze (MWM) to test spatial memory, aortic collagen, elastin (histochemistry), and left ventricle (LV) mRNA expression (qPCR) were assessed at 3- & 12-mo. Data analyses: linear mixed-effect 2-way ANOVA, t-test & linear regression (LR) modeling. A 2-sided p<0.05 was considered significant. Results: SBP, PWV, aortic weight, wall thickness and collagen/elastin ratio were higher in DSS-3 vs. SD-3, and in DSS-12 vs. DSS-3. RWT and LV expression of pro-fibrotic, inflammatory and senescence genes were higher in DSS-12 vs. DSS-3 and vs. SD-12 (Table). DSS-12 spent more time to find a hidden platform in MWM vs. SD-12; their impaired spatial hippocampal memory was positively associated with PWV and LV mass by LR analysis. Conclusions: EVA, indexed as higher BP, PWV and aortic remodeling was associated with early CV aging, manifested by activation of LV senescence, inflammatory and pro-fibrotic genes and by higher rates of age-associated changes in BP, RWT and LV mass in DSS vs. SD. In DSS, early CV aging was associated with memory decline.

Nogo-A, B, and C are well described members of the reticulon family of proteins, most well known for their negative regulatory effects on central nervous system (CNS) neurite outgrowth and repair following injury. Recent research indicates a relationship between Nogo-proteins and inflammation. Microglia, the brain's immune cells and inflammation-competent compartment, express Nogo protein, although specific roles of the Nogo in these cells is understudied. To examine inflammation-related effects of Nogo, we generated a microglial-specific inducible Nogo KO (MinoKO) mouse and challenged the mouse with a controlled cortical impact (CCI) traumatic brain injury (TBI). Histological analysis shows no difference in brain lesion sizes between MinoKO-CCI and Control-CCI mice, although MinoKO-CCI mice do not exhibit the levels of ipsilateral lateral ventricle enlargement as injury matched controls. Microglial Nogo-KO results in decreased lateral ventricle enlargement, microglial and astrocyte immunoreactivity, and increased microglial morphological complexity compared to injury matched controls, suggesting decreased tissue inflammation. Behaviorally, healthy MinoKO mice do not differ from control mice, but automated tracking of movement around the home cage and stereotypic behavior, such as grooming and eating (termed cage "activation"), following CCI is significantly elevated. Asymmetrical motor function, a deficit typical of unilaterally brain lesioned rodents, was not detected in CCI injured MinoKO mice, while the phenomenon was present in CCI injured controls 1-week post-injury. Overall, our studies show microglial Nogo as a negative regulator of recovery following brain injury. To date, this is the first evaluation of the roles microglial specific Nogo in a rodent injury model.

The prevalence of cognitive impairment (CI) and dementia in end-stage chronic kidney disease (CKD) has been estimated at 30-60%. Cardiovascular dysfunction accompanies CKD and contributes to CI in humans and animal models. Since CKD occurs more often in females in clinical studies, the aim of this study was to determine whether cardiovascular and renal remodeling is associated with cognitive performance in the female rats with CKD. Four-month-old female Sprague-Dawley rats were fed with 0.25% adenine diet to induce CKD (n = 19) or a regular control diet (n = 16; CTRL) for 8weeks. Body weight (BW), blood pressure (BP), heart rate (HR), blood urea nitrogen (BUN), sodium, potassium, creatinine, hematocrit, estradiol, and behavioral tests were assessed at the end of the study. The level of anxiety was tested in open field test (OFT) and elevated plus maze (EPM). Spatial memory was tested by the ability to find a hidden platform in Morris water maze (MWM). The data were analyzed by two-tailed unpaired t-test and linear regression analysis (LRA). CKD was associated with higher creatinine and BUN, lower hematocrit, and enlarged hearts, aortae and kidneys vs. CTRL (Table 1). There was no difference in BP, estradiol, sodium and potassium, MWM, OFT and EPM performance between the groups. However, the LRA revealed the association of higher heart weights with a reduced spatial memory and higher anxiety level in both CTRL and CKD (Table 2; Figure 1A,B). The association of higher aortic weight with a reduced spatial memory, and higher kidney weight with higher anxiety levels was demonstrated in CKD only (Table 2; Figure 1C,D). Estradiol was associated with better spatial memory in CKD (LRA: R 2 = 0.264; p = 0.04). Anxiety-like behavior and spatial memory were associated with cardiovascular remodeling in young female rats with CKD. We suggest that (1) CKD stimulates development of cardiovascular remodeling, which may affect blood supply of cortex and hippocampus, responsible for anxiety and spatial memory, and (2) estradiol may contribute to a better cognitive performance in the young CKD female rats. The future direction is to investigate whether CKD influences the trajectory of neurocognitive and cardiovascular aging. Supported by NIA/NIH/IRP

Alzheimer’s disease (AD) is characterized by brain amyloid beta plaque formation, neuroinflammation and neuronal degradation, which lead to cognitive impairment and decline in normal circadian rhythm (CR). Bioactive steroid marinobufagenin (MBG) modulates neuroinflammation. In 16‐mo old double transgenic APPswe/PS1dE9 AD mice with advanced AD, amyloid precursor protein (APP) and interleukin 6 (IL6) mRNAs were upregulated vs. wild type (WT) control, and treatment with MBG reduced mRNA expression. Here, we investigated whether treatment with MBG at early‐stage AD may impact AD development in this AD mouse model.

The prevalence of cognitive impairment (CI) and dementia in end-stage chronic kidney disease (CKD) has been estimated at 30-60%. Cardiovascular diseases (CVD) including increased central arterial stiffness (CAS) accompany CKD development and contribute to CI. Elevated pulse wave velocity (PWV) is associated with higher mortality in CVD and CKD independently of blood pressure (BP). Marinobufagenin (MBG) is a pro-fibrotic factor, which increases in CKD and contributes to CAS. The aim of this study was to determine whether CKD potentiates CI development via CAS and cardiovascular remodeling in a rat model of CKD. Four months old male Sprague-Dawley rats were fed with 0.25% adenine (n=19; CKD group) diet to induce CKD or regular diet (n=16; CTRL group) for 8 weeks. Body weight (BW), BP, heart rate (HR), aortic PWV (aPWV), and behavioral tests were conducted at the end of the study. The level of anxiety was tested in an open field test (OFT). Morris water maze (MWM) was used to test spatial memory. Blood was collected for measurements of plasma sodium, potassium, blood urea nitrogen (BUN), hematocrit and MBG. The data were analyzed using two-tailed unpaired t-test and linear regression. Animals in the CKD group had higher levels of plasma creatinine and BUN, which indicate the development of CKD, higher plasma sodium, potassium, and MBG, and higher aPWV, lower hemoglobin, hematocrit, BW, HR, enlarged hearts, aortae, and kidneys, vs. CTRL group (Table 1). BP was similar in both groups. .Rats in CKD group spent less time in the center of open field compared to their CTRL counterparts, indicating increased anxiety-like behavior (Figure 1 A, B). Although there was no difference in performance in MWM between the groups, there was a positive correlation between aortic weight and ability to find a hidden platform in the CKD group (Figure 1C). We demonstrated that CKD development in young Sprague-Dawley rats was accompanied by increased CAS, estimated as aPWV, which developed in blood pressure-independent manner. Higher PWV was associated with a higher level of anxiety, and aortic tissue remodeling was associated with spatial memory in CKD model. Supported by NIH/NIA IRP

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13024-022-00564-6.

Double-mutant mice (APPswe/PS1dE9; 2xTg-AD) represent a model of Alzheimer’s disease (AD). 2xTg-AD mice develop progressive accumulation of amyloid plaques and cognitive impairment (CI) with age in >12 months old animals. The aim of the present study was to investigate the associations of CI and cardiovascular function in 2xTg-AD mice. Aortic pulse wave velocity (aPWV), an estimation of aortic stiffness, and cardiac parameters were measured by echocardiography in 16-mo old male 2xTg-AD (n=11) and wild type (WT; n=17) mice. Spatial memory (using Morris water maze; MWM) and the anxiety level (using open field test; OFT) were assessed. The relationship between cardiovascular and behavioral parameters were modeled using a linear regression analysis (LRA) with a backward elimination. P-values <0.05 were considered significant, and 0.05≤P<0.1 were considered near significant and were included in the models. 2xTg-AD mice exhibited an increase in aPWV and had a thicker left ventricle (LV) posterior wall in diastole (LVPWd) and narrower LV internal diameter (LVIDd) vs. WT mice (Table 1). 2xTg-AD mice spent less time in the center of OF vs. WT mice (Table 1). LRA revealed a negative association between time spent in the center of OF and LVPWd, and a positive association with LV volume in diastole (LVvold) in 2xTg-AD mice (Table 2). In MWM, 2xTg-AD mice exhibited impaired spatial memory estimated as prolonged average escape latency during their training vs. WT counterparts (Table 1). Although there was no difference between performance in the MWM probe trial, LRA showed a negative association between LVPWd and the mean distance from the platform in the probe trial in 2xTg-AD mice, and a positive association of LVPWd with number of entries to the platform zone (Table 2). There was a positive association between aPWV and mean distance from the platform in the probe trial in both 2xTg-AD and WT mice. LRA results indicate that LV remodeling is associated with anxiety-like behavior in 2xTg-AD mice, but not with spatial memory impairment. Positive association of aPWV with spatial memory impairment in both groups suggests that aortic stiffness contributes to the age-associated CI. Supported by the NIH/NIA IRP.

Short telomeres induce a DNA damage response (DDR) that evokes apoptosis and senescence in human cells. An extant question is the contribution of telomere dysfunction-induced DDR to the phenotypes observed in aging and telomere biology disorders. One candidate is RAP1, a telomere-associated protein that also controls transcription at extratelomeric regions. To distinguish these roles, we generated a knockin mouse carrying a mutated Rap1, which was incapable of binding telomeres and did not result in eroded telomeres or a DDR. Primary Rap1 knockin embryonic fibroblasts showed decreased RAP1 expression and re-localization away from telomeres, with an increased cytosolic distribution akin to that observed in human fibroblasts undergoing telomere erosion. Rap1 knockin mice were viable, but exhibited transcriptomic alterations, proinflammatory cytokine/chemokine signaling, reduced lifespan, and decreased healthspan with increased body weight/fasting blood glucose levels, spontaneous tumor incidence, and behavioral deficits. Taken together, our data present mechanisms distinct from telomere-induced DDR that underlie age-related phenotypes.