Retraction Notice: The E-learning for Alzheimer's Disease

FigureThe concept of peer review can be interpreted very differently among nurses and healthcare professionals. Some think of a subject expert reviewing a manuscript for a journal's editorial staff. Others think of regulatory bodies requiring hospitals to have an internal process to ensure that healthcare team members are competent and able to perform within their scope of practice.1 Still others think of peer review as a quality assurance process in which healthcare team members audit each other's documentation to validate care standardization. We provide insight into a nursing peer review process designed to evaluate performance, and the journey to its implementation. A well-defined peer review process and tool, utilized in conjunction with a nurse's annual performance evaluation, is one way to infuse meaningful peer input into a performance appraisal. This system allows nurses to provide insight into one another's strengths and opportunities for growth. A detailed approach was used to create, develop, and sustain a nursing peer review program that's flexible enough to be used by all staff members within a pediatric hospital system. In addition to promoting professional growth among nursing staff, this process also meets the current peer review standards set by the Magnet Recognition Program® and The Joint Commission. The ultimate goal of sharing this information is to help other organizations that are just beginning the peer review process and those that have struggled in the past with development and implementation to bring about a sustainable change. This, in turn, will promote nursing cohesiveness and professionalism as we work together to bring healthcare into a new era. Organizational standardization Our organization embarked on an initiative to create a standardized peer review process that would be utilized by all nursing departments. The process needed to be integrated organizationally and applicable to clinical nurses within both inpatient and outpatient environments. This journey began with a review of the current literature and an examination of the current peer review practice at other Magnet® facilities. Through this process, it was discovered that the majority of these facilities utilized and defined peer review in a variety of ways. We identified variation in the management of the peer review process within our own organization. Acknowledging the vast array of discrepancies within and external to the organization, a task force of clinical nurses was developed to redefine the way our organization administered the clinical nurse peer review process. This task force also included two leadership liaisons who served as resources to the clinical nurses during this development and provided insight into the management side of the peer review process. There were four steps in our process: (1) defining a peer, (2) developing a peer review form, (3) transforming the process, and (4) implementing the process. Who's a peer? The first step in our work involved evaluating, discussing, and reaching a consensus on the definition of peer. In order to standardize the peer review process, the task force recognized a true definition was needed to measure success with the new process. Looking at previous peer review practice in the organization, many nurses and department directors had different definitions and ideas of what it meant to be a peer. Some departments included other disciplines in a nurse's specialty for evaluations, whereas others utilized only fellow nursing staff members. The task force agreed that the purpose of peer review is to foster professional growth and development among staff members by utilizing a process through which measurable outcomes are assessed. After much dialog, the task force adopted the definition of peer utilized by the American Nurses Association, which defines a peer as an individual of the same rank or standing according to the established standards of practice.2 Form development The next step in redefining the peer review process was to develop a new peer review tool that could be transferrable and applicable among the various nursing specialties and departments. Key areas identified by the task force for development of this tool included creating a short, concise form that's easy to understand with limited directions and applicable to all clinical nursing departments. To achieve this goal, the task force worked collaboratively to establish eight domains that would provide nurses with a peer evaluation framework. These domains were established through open dialog, including question-and-answer sessions, review of current job descriptions, and evaluation of other tools utilized by various Magnet facilities. Through this work, a common set of core expectations were identified and utilized in the development of each domain. These domains encompass the essential clinical nurse job functions, behavioral competencies, and basic roles and responsibilities throughout the organization. The domains can be found in Table 1.Table 1: The eight domains of peer evaluationTo further guide and support high-quality peer feedback, three to five specific, measurable objectives were created and listed under each domain for nurses to measure performance. These objectives were developed to guide peers in evaluating each nurse by providing focused, pertinent feedback. The task force wanted to eliminate vague, nonspecific feedback that didn't facilitate the identification of future growth opportunities. The objectives created by the task force assist peers in identifying evidence from the nurse's daily work, communication, time management, and interdisciplinary interactions. Each domain also included a comment field, allowing nurses the autonomy to provide open-ended feedback and elaborate on outstanding work or opportunities for the employee's growth and improvement. The comment section was extremely important in the solicitation of meaningful feedback because it allowed nurses to provide examples to reinforce the ratings selected for the objectives. The directions on the new tool clearly state that comments are mandatory for certain ratings to allow for elaboration and examples. The task force believed a Likert rating scale was essential to standardize the peer review process. The previous process utilized a vague, numerical score that hadn't historically provided nurses with adequate descriptions of their work ethic and performance. Lower scores were considered negative responses, whereas higher scores equated to positive responses. After review of the current literature, the task force employed a 4-point Likert scale comprising "not met," "approaching," "meets expectations," and "exceeds expectations." In addition to the scaled questions, an open-ended question "Do you feel comfortable working with this nurse?" was added to the form. Utilizing a mixed-method methodology, Likert scale, and open-ended question format allowed the evaluating nurse a better opportunity to provide real-life contextual examples related to the evaluated nurse's care.3 Process transformation After the peer evaluation tool was created, the task force focused its attention on creating a framework to aid departments in implementing the new peer review process. Throughout our hospital, there are units of vastly different sizes. Some nursing departments have four to six clinical nurses, whereas other departments have as many as 150 to 200 clinical nurses on staff. The variability in staff sizes meant that the task force had to be creative in determining how many peer reviewers should evaluate each nurse annually and how these reviewers should be selected. With the new process, each nurse receives feedback from two to four RNs. Limiting the number of peer evaluations eliminated the previous dissatisfaction and/or barrier of evaluators being asked to fill out 20 to 30 peer evaluations a month due to exceedingly large nursing departments. The task force also allowed clinical nurses to select one to two peers of their choice to provide feedback; the management team selected the remaining peers. Implementation After the task force completed the new peer review tool and process recommendations, the nursing department directors and the CNO gave the approval for implementation. The standardized peer review form, along with the revised process, was implemented using various educational modalities. The first presentation was provided to the inpatient and outpatient nursing directors to inform them about the new form and the revised process. The directors were provided with handouts outlining the changes and educational fact sheets for the staff members to use as a reference. The task force increased its availability to ensure educational consistency to all clinical nurses by attending and presenting at unit-based councils, charge nurse meetings, and department-wide staff development programs. The feedback received from the different educational presentations was extremely positive. Feedback discussed the tool's ease of use, applicability to all nursing departments, appropriate form length, and measurable objectives that allowed nurses to comment on focused job roles and responsibilities. Other feedback included the improved functionality of the new rating scale and the process change that limited the number of requests for peer evaluations. Some directors expressed resistance to changing their current peer review practice. Certain directors thought feedback from four nurses wasn't enough if the department had a high number of nursing staff members. After an open discussion with the task force chairperson and the directors of large departments, it was agreed that meaningful feedback from four people would be adequate. Other directors mentioned that they liked the idea of adding specific clinical skills for peer evaluation. However, we couldn't add specific skills because they wouldn't universally apply to the various nursing department specialties. The task force collected all comments and feedback, and created a frequently asked questions document to address these concerns and explain the thought process behind the decisions made about the tool and recommendations. Directors were then provided with answers to and rationales for their specific questions and concerns, creating a consistent message and clarity to all departments. All education and implementation occurred over the course of 4 months. During this time, the task force worked with web development to formulate an electronic version of the peer evaluation document for the purpose of online submission. The electronic document was widely popular because it eliminated the use of paper and facilitated tool access for all clinical nurses. Staff members were able to complete the tool online and submit the evaluation through the organization's intranet directly to the person who requested the feedback. The task force also concluded that in order for this new tool and process to remain functional and meaningful, continued evaluation of its use would be essential. Reaching the top As we diligently work to move the nursing profession forward, it's important to remember that peer review can positively impact not only an individual's nursing practice, but also an entire hospital system. Nurses are at the forefront of healthcare transformation and are integral to sustainable practice improvement. By empowering clinical nurses to lead this initiative, we've been able to successfully introduce, develop, and support a valuable peer review process across our organization. Utilizing a comprehensive peer review tool can help organizations improve patient outcomes and patient satisfaction.

The American Journal of Psychiatry Residents' Journal: Training the Next Generation of Academic Psychiatrists.

Civility in Nursing Peer Review: Giving and Receiving Feedback

Alzheimer’s Disease (AD) is the most common form of dementia and a major cause of disability and death among the older population. In addition, Cardiovascular dieseases (CVDs) and their risk factors are associated with an increased risk of the progression of AD and cognitive impairment. Despite this, studying the combination of these diseases constitutes a clinical challenge, and investigations to understand the mechanistic pathways for the cause-effect and/or shared pathology between them remains an active area of research. One form of AD, familial AD, is linked with an early onset AD (EOAD) pathology (<65years) that manifests through pathogenic mutations in the genes encoding the amyloid precursor protein (APP) and the g-secretase complex enzymes presenilin (PSEN)1 and PSEN2 which result in the increased production of central amyloid β (Aβ) peptides. There is increasing evidence that amyloid deposition in peripheral vessels has powerful structural effects in CVDs which, in turn, increase the risk of cognitive decline later in life. With this premise, we hypothesized that vascular dysfunction would be observed in the resistance arteries prior to the development of EOAD regardless of sex. To test the hypothesis, mesenteric resistance arteries (MRA) were isolated from male and female early onset AD mice (B6.CApptm1Dbo Tg(APPswe, PSEN1dE9)85Dbo/Mmjax) prior to (9 weeks of age) and after the onset of AD (28 weeks of age). Vascular function was evaluated using wire myography and concentration-effect curves to acetylcholine, phenylephrine and to U46619, a thromboxane A2 analog, were performed. Data were analyzed using non-linear regression analysis and maximum response (Rmax) analyzed by Student t test (p<0.05*). Arteries from 9-week-old AD mice showed impaired acetylcholine-induced relaxation and phenylephrine-induced hypocontractility for males [Rmax: control 11.72±0.9 vs. AD 7.70±0.8*, n=3-4]. Females presented a similar tendency of phenylephrine-induced hypocontractility. However, a “catch-up phenomenon” was observed and resulted in phenylephrine-induced hypercontractility in arteries from 28-weeks-old AD mice Males [Rmax: control 9.34±1.3 vs. AD 14.5±0.4*, n=3-5] and Females [Rmax: control 10.4± 2.8 vs. AD 13.8±1.5mN, n=3-4]. The same hypercontractility profile was observed in the arteries isolated from 28-weeks-old AD mice for U46619 agonist in both males [Rmax: control 12.4±1.5 vs. AD 15.6± 0.6*mN, n=3-5] and the females [Rmax: control 9.3± 1.7 vs. AD 14.3±1.9mN, n=3-4]. Overall, our data suggest that vascular dysfunction, which may lead to disrupted blood flow, nutrients and oxygen delivery to the brain, could contribute to the genesis and maintenance of AD. R00GM118885, R01HL149762, R00HL151889, and NHLBI (R00HL151889) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Peer Review: The Best of the Blemished?

Aging and Alzheimer disease (AD) are both characterized by progressive reduction in nitric oxide bioavailability and endothelial function impairment. Promising studies on young healthy individuals underly the positive effect of dietary nitrate supplementation on endothelial function. However, the pharmacokinetics of the plasma nitrate and nitrite (PN) and the accompanying endothelial responsiveness following the oral nitrate ingestion in healthy elderly (HE) and patients with AD is not clear. Our hypothesis was that due to the reduction of nitric oxide bioavailability during aging and AD, an equal dose of oral nitrate (ON) would ameliorate the endothelial responsiveness more in the HE and even more in patients with AD in comparison to healthy young subjects (HY). Therefore, with the aim of investigating the pharmacokinetics of PN and the time-course endothelial responsiveness in response to a single dose ON, 10 HY (25±4 YRS), 10 HE (72±8 YRS) and 13 AD (73±7 YRS) were recruited. PN levels and endothelial responsiveness (single-passive leg movement (ΔPLM)) were measured in the recruited individuals prior to (T0) and hourly for 4 hours (T1, T2, T3, and T4) after: a) a single dose of ON; and b) a single dose of placebo. As expected at T0 both PN and ΔPLM were significantly reduced in the HE and even more reduced in the AD in comparison to the HY (all p<0.001). No changes in PN nor ΔPLM were detected in any group following placebo intake. PN increased significantly in all three groups at T1 (p<0.001) and constantly increased up to T4, but no differences were detected between time points T1 to T4 in any group. ΔPLM increased significantly in all three groups at T2, reaching highest values at T4 (p<0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to HY (p<0.0001) and HE (p<0.001). Significant correlation between PN and ΔPLM was found (p<0.001, R2=0.1654). Contrary to our hypothesis, the results of this study suggest that the PN pharmacokinetics following a single dose of ON is similar in HY, HE and AD. Moreover, the expected time-course amelioration of the endothelial responsiveness was reduced in the HE and even more reduced in the AD, suggesting that other factors, rather than the nitric oxide bioavailability, are playing a role in the age- and AD-related vascular dysfunction. Ricerca di Base 2017 - RBVR17XRSA - Effectiveness of exercise and nitrate supplementation on progression of dementia in patients with Alzheimer’s disease. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Alzheimer’s disease (AD) is the most prevalent form of dementia and currently impacts ~50 million people worldwide. AD is associated with impaired cerebrovascular function which underscores diminished delivery of blood oxygen and nutrients to and throughout the brain. Thus, we hypothesized that cerebrovascular miRNAs indicate early onset of AD pathology while corresponding to pathways of cerebrovascular growth, structure, and function. Total RNA was isolated from brain vessels of 3xTg-AD mice [Young, 1-2 mo; cognitive impairment (CI), 4-5 mo; extracellular amyloid-β plaques (Aβ), 6-8 mo; plaques + neurofibrillary tangles (AβT), 12-15 mo; n=3 males & 3 females per group]. Fifty-four cerebrovascular miRNAs detected by NanoString technology (nCounter miRNA Expression panel) were mapped to their known mRNA targets using Ingenuity Pathway Analysis. With the premise that AD is a neurovascular disorder, we sought mRNA targets along both the canonical Cardiovascular (Cardio; 15±2 targets per miRNA) and Nervous System (Neuro; 19±2 targets per miRNA) signaling strings with an overlap of 9±1 targets per miRNA among respective pathways. We found that eleven miRNAs were significantly ( p<0.05) downregulated in AD (Aβ + AβT) versus Pre-AD (Young + CI) animals. In particular, let-7d, miR-99a, miR-132, and miR-181a indicated onset of AD (Aβ group) versus Young or CI. Further, miR-133a delineated CI from Young, highlighting the ability of miRNA markers to track early cerebrovascular alterations prior to AD as well. In contrast to the stability of smooth muscle-selective miRNAs (miR-143, miR-145), endothelial miRNAs (miR-23, miR-27a, miR-126) decreased with AD pathology and they target members of the PDE, PDGF, SMAD, and VEGF families. The most prominent individual mRNA markers for distinguishing onset of AD pathology while regulated by ≥3 cerebrovascular miRNAs include Slc6a1, Grin2b, Igf1r, and Smad5. The absolute difference in target overlap among respective Cardio and Neuro pathways was significantly ( p<0.05) higher for all miRNAs that marked AD pathology (28±7%) relative to miRNAs stably expressed throughout (15±2%), suggesting a divergence in overall Cardio and Neuro signaling in AD relative to Pre-AD conditions. In conclusion, miRNAs selective for regulation of endothelial function and respective downstream mRNA/protein targets support a molecular basis for dysregulated cerebral blood flow regulation coupled with enhanced cell growth, proliferation, and inflammation. Accordingly, pathways associated with cerebrovascular miRNAs and their respective mRNA targets advance mechanistic and therapeutic insight for resolving early AD development. NIH Grants: R00AG047198, R56AG062169 & R01AG073230 (EJB). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A hallmark of professional practice, nursing peer review is the process by which practicing RNs systematically assess, monitor, and give feedback to peers about the quality of nursing care measured against professional standards of practice.1 Nursing peer review supports self-regulation of clinical

Alzheimer’s disease (AD) is a progressive neurocognitive disease characterized by amyloid beta plaques and neurofibrillary tangles in the brain along with inflammation both in the brain and systemically. This has led to the theory of microbial communities or infections as being causative in the development of neuroinflammation as well as immunosenescence and inflamm-aging seen in AD. Our own research has demonstrated a decreased abundance of anti-inflammatory taxa and an increased abundance of pro-inflammatory taxa in the gut microbiome of AD patients. However, it is unclear how the AD microbiome exerts effects on the central nervous system. To address this gap in knowledge we have performed gut microbiome profiling, analysis of immune cell populations in serum, blood cytokine profiling, and cognitive assessments of AD older adults at 90-day intervals. In our early data collected from this ongoing study we have observed changes in B-cell populations with an increased abundance of class-switched B-cells in older adults with greater levels of cognitive impairment. We have further demonstrated that colonization of mice with the microbiome of AD older adults promotes B-cell class-switching when compared with cognitively impaired older adults without AD. Additionally, we have discovered a loss of phytoestrogen-metabolizing bacteria such as Adlercreutzia equolifaciens among AD older adults with rapidly progressing dementia. Phytoestrogens have been previously identified in protecting the intestinal epithelium from oxidative stress and epithelial permeability. Our preliminary studies have suggested that that the phytoestrogen (s)-equol, produced by A. equolifaciens, confers resistance to epithelial damage in the setting of bacterial lipopolysaccharide. Thus, we hypothesize that Adlercreutzia equolifaciens and similar phytoestrogen-metabolizing bacteria maintain epithelial homeostasis in the setting of inflammation while a gain of pro-inflammatory taxa in AD leads to intestinal barrier disruption, increased antigen presentation, immune cell dysregulation, and ultimately cognitive decline. This continuing work aims to further establish the connection between AD related neurocognitive decline, the microbiome, and immune system. This research was funded by grant numbers R01DK125407, R01AG067483, and 5T32A1007349-31 from the National Institutes of Health This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Clinical and rodent studies suggest that the brain renin-angiotensin system (bRAS) may play a role in Alzheimer’s disease (AD) pathology and cognitive decline. This study utilized recently developed novel transgenic AD-BXD mouse strains, designed to enhance understanding of genetic diversity, in susceptibility and resiliency factors, in AD. Methods: B6-5XFAD mice were crossed with 28 BXD strains to generate a population of AD-BXDs (Neuner et al, 2019;). Bulk RNA sequencing (RNAseq) data from the hippocampus of male and female mice at 6 and 14 months of age were evaluated for bRAS-related protein gene expression changes (GEO accession numbers: GSE101144, GSE119215, and GSE119408). Comparisons between AD gene carriers (AD-BXD, n = 135) vs noncarrier littermates (Ntg-BXD, n = 157) assessed differential expression of bRAS-related genes; Agtr1b, AP-A, Rnpep, Ace, Agtr1a, Agtr2, Ren, Agt, AP-N, Ace2, Atp6ap2, Agtrap, Adam17, MasR, Lnpep, and Nr3c2. Single-nucleus RNA sequencing data from the Religious Orders Study and Memory and Aging Project (ROS/MAP; PMID: 37774677; n = 427) was also used. Parallel comparison of bRAS-related genes were analyzed in amyloid+ and amyloid- populations from the human ROS/MAP data base. Results: Expression of the primary receptor subtypes of the bRAS, Agtr1 and Agtr2, were unchanged, however a significant main effect of genotype was observed in the expression of the mineralocorticoid receptor (Nr3c2), Mas receptor (MasR), pro-renin receptor (Atp6ap2), and the angiotensin type IV receptor (Lnpep) were significantly downregulated in AD-BXD mice compared to Ntg-BXD mice, suggesting a potential moderation of function of the bRAS in AD mice. A significant main effect of sex was observed in the expression of Adam17, MasR, Lnpep, and Nr3c2. Interaction analysis revealed a significant genotype x age interaction for the expression of Agtrap, Adam17, and MasR, indicating potential age-specific roles in AD pathophysiology. In human cortical tissue, expression of MasR and Atp6ap2 was also significantly decreased in individuals with amyloid+ status (MasR: -0.02 logFC, adj-p = 0.03; Atp6ap2: -0.03 logFC, adj-p = 0.005). Conclusions: Our findings reveal significant changes gene expression of bRAS related receptors and regulatory proteins in a mouse model exhibiting genetic, transcriptomic, and phenotypic diversity. This study provides valuable insights into the regulatory mechanisms of the bRAS in AD pathology and may provide novel therapeutic targets for preventing or delaying the onset and progression of AD. NIH - NIA 1R21AG086859-01 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Dispirited Away: The Peer Review Process

Alzheimer’s disease (AD) is the most common form of dementia and among the leading mortalities in the US. There is growing evidence supporting a connection between AD and cardiovascular disease (CVD). Variant isoforms of apolipoprotein E (APOE) are risk factors for AD and CVD. Compared to the most common APOE isoform, APOE3 (E3), APOE4 (E4) increases AD risk. In order to study APOE-mediated processes, posterior cerebral arteries (PCA) and common carotid arteries (CCA) were isolated from mice expressing human-ApoE targeted replacement of APOE3 (B6.129P2- Apoetm2(APOE*3)Mae N8) and APOE4 (B6.129P2- Apoetm3(APOE*4)Mae N8)(Taconic Labs). Our objective was to determine whether the E3 and E4 allele cause different mechanical properties in the absence of extracellular Ca2+ in the PCA and CCA isolated from young (Y, 3-4mo), adult (Ad, 12-15mo), and aged (Ag, 18-22mo), homozygous E3 and E4, male and female mice. We hypothesized that E4 would alter PCA and CCA structure/function when compared to age matched E3 cohorts. 5-8mm segments of PCA and CCA were isolated, cleaned of connective tissue, cannulated, and placed into an arteriograph. Upon equilibration, all vessels were challenged with 60mM [K+] to assess viability. Vessels not responding to 60mM [K+] were discarded. Mechanical characteristics, including lumen diameter (LD), wall thickness (WT), passive distensibility (PD), and stress/strain (S/S) were measured at intraluminal pressures ranging from 10-140mmHg. We observed no statistical differences in LD, PD, or S/S in PCAs and CCAs of Y and Ad, E3 and E4 mice. For LD and WT, Ag E3 was greater than Ag E4 (p<0.05). In contrast, LD in PCAs and CCAs of Ag E3 mice was larger than in Ag E4 mice (p<0.05). We further observed that PD and S/S in CCAs from Ag E3 was greater than in Ag E4 mice (p<0.05), whereas there was no difference in PD and S/S in PCAs isolated from Ag E3 or E4 mice. The WT of PCA in Y E4 was significantly greater than Y E3 mice (p<0.05). In contrast, WT in Ag E3 mice was larger than Ag E4 mice (p<0.05). There was no difference between WT of Ad E3 and E4 mice. The WT of CCAs was significantly greater in Ag E3 vs Ag E4 mice (p<0.05). There is no difference in WT in CCAs from Y (E3 vs E4) or Ad (E3 vs E4) mice. This data indicates aging has minimal effect on mechanical properties in the PCA. In contrast, CCAs in Ag E4 exhibited greater arterial stiffening as indicated by a decrease in their distensibility and leftward shift in S/S, as evidenced by greater stress for given amount of strain observed in PCAs of Ag E4 mice at increased intraluminal pressures. ABRC/ADHS18-205211 (JVE, TBJ, CBJ, DME), Arizona Alzheimer's Consortium (funded by the Arizona Department of Health Services, Contract No. CTR040636) and matching funds from Midwestern University (DME), Biomedical Sciences Program (BG, LJS, DME), Biomedical Sciences Start-up Funds (DME). LJS and ASH equally contributed as first authors. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder characterized by vascular rarefaction and cognitive decline. Oxidative stress and mitochondrial dysfunction are crucial in AD progression, however how AD alters vascular cell survival during acute oxidative stress remains undefined. While healthy aging enhances vascular resilience to oxidative stress, we hypothesized that AD increases apoptosis of smooth muscle (SMC) and endothelial cells (EC) to acute oxidative stress by increasing mitochondrial ROS production and depolarization of mitochondrial membrane potential (ΔΨ m ). Posterior cerebral arteries (PCA; ~80 µm diameter) from male and female 3xTG AD mice—examined at various stages of disease progression, including young (YH - 2-3 months), cognitively impaired (CI - 4-5 months) and amyloid beta plaques (Aβ - 6-8 months)—were isolated, cannulated, and pressurized to 90 cm H 2 O at 36°C. The effect of AD on resting mitochondrial ROS production in PCAs was evaluated with MitoSox (5 µM). ROS production was modestly augmented (p<0.05) in vessels from CI mice and further augmented in Aβ mice of both sexes. SMC and EC death were quantified using Hoechst 33342 (1 µM - stains all nuclei) and propidium iodide (1 µM - staining dead nuclei) after 50 min exposure to H 2 O 2 (200 µM). SMC and EC death were <10% in young healthy control PCAs from males and females. Apoptosis was enhanced in both cell types in vessels from male Aβ mice (~ 20%) compared to YH and CI (<=10%). While SMCs from female CI mice exhibit significantly (p<0.05) higher death (~ 20%) compared to YH, SMCs from Aβ mice did not have greater susceptibility to H 2 O 2 (<10% cell death). EC death in females showed similar trends. Given that depolarization of ΔΨ m is a critical event for the initiation of intrinsic apoptosis, we assessed changes in ΔΨ m during exposure to H 2 O 2 with tetramethylrhodamine methyl ester (TMRM, 10 nM). For males, exposure to H 2 O 2 exasperated depolarization of ΔΨ m in pressurized PCAs from Aβ compared to CI or YH mice. In females, H 2 O 2 evoked the greatest ΔΨ m depolarization in PCAs from CI mice consistent with the high cell death in these vessels. We conclude that AD increases ROS production in cerebral arteries and enhances sensitivity to ROS-mediated cell death. Furthermore, apoptosis is elevated in different phases of AD in males and females providing insight into the progression of vessel rarefaction linked to cognitive decline. AARG-NTF-23-1148948 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Despite being the most common form of dementia in the elderly, mechanisms causing AD remain elusive. Emerging evidence have associated brain renin-angiotensin system (RAS) to AD neuropathology. RAS actions are predominantly mediated by angiotensin II (Ang II) binding to type 1 receptors. Previously, we have observed that human apolipoprotein E4-knockin (risk factor for AD) mice develop progressive hypertension and increases in Ang II levels in CSF with aging [FASEB J 36(S1): R3532]. Thus, we hypothesize that Ang II-mediated hypertension contributes to cognitive decline in AD. We have generated a novel transgenic mouse model of AD i.e. 3XE4 by breeding E4-knockin mouse with APPsw, PS1dE9, and tauP301S transgenes, to mimic human AD pathology in mice. Blood pressure (BP) and heart rate (HR) were measured by radiotelemetry in 3XE4 (n=6) and control 3XE3 (n=6) mice, before and after 28-days of Ang II infusion (1000 ng/kg/min, osmotic pump). Diurnal BP variability was calculated as the difference between night-time (11:00 PM-3:00 AM) and day-time (8:00 AM-12:00 PM). Cardiac vagal and sympathetic tones were calculated as changes in HR with atropine and propranolol (1 mg/kg each, IP), respectively. Cardiac function (echocardiography) and cognitive behavior (novel object recognition test) were measured. At baseline, BP was similar in control (127±11 mmHg) and 3XE4 (123±5 mmHg) mice. Unlike the control mice, 3XE4 mice exhibit reduced vagal tone (ΔHR= +119±22 vs. +25±24 bpm) and increased sympathetic tone (ΔHR= -76±33 vs. -212±40 bpm), which worsens with Ang II (p<0.05 vs. baseline). Interestingly, Ang II increased BP (24%), induced LV hypertrophy (26%), impaired diurnal BP variability, and evoked learning and memory deficits; albeit only in the 3XE4 mice (p<0.05 vs. control mice). These results demonstrate that Ang II-mediated hypertension and autonomic dysfunction likely exacerbate disease progression and cognitive decline in the 3XE4 mouse model of AD. Therefore, our study provides a proof-of- concept in delineating the association of ApoE4 genotype and Ang II with Alzheimer’s disease. NIH R01HL149677 and R21AG070188. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

While therapeutic approaches targeting neurodegenerative mechanisms associated with cognitive impairment in Alzheimer's disease (AD) have been intensively explored, other comorbidities closely linked to AD progression, such as sleep-disordered breathing and autonomic dysfunction, have not been thoroughly investigated. In preliminary studies, we showed an increase in neural activity of catecholaminergic premotor neurons located in the rostral ventrolateral medulla region (RVLM-C1), a main region involved in cardiorespiratory regulation, in experimental AD. Therefore, in the present study, we aimed first to characterize cardiorespiratory function in AD patients and then to determine the role of RVLM-C1 neurons in autonomic and sleep-disordered breathing in APP/PS1 double transgenic mice, an experimental model showing AD-like pathology. Sixteen subjects (8 AD and 8 age-matched controls) were enrolled to assess sleep breathing disorders and to record cardiac autonomic function. Whole-body plethysmography and blood pressure monitoring in freely moving mice were used to study sleep-associated cardiorespiratory disorders. Bilateral stereotaxic injections of anti-dopamine β-hydroxylase-saporin (DβH-SAP) into the RVLM were used to selectively destroy C1 neurons. Compared to age-matched healthy subjects, patients with AD showed larger increases in neural sympathetic discharges during autonomic testing. In addition, heart rate variability analysis in AD patients showed a shift in spectral components towards a more sympathetic influence. Remarkably, we found that autonomic function impairment in the APP/PS1 mice resembles what we found in AD patients. Compared to wild type (WT), APP/PS1 mice displayed sympatho-excitation (ΔHR: -80±5 vs -125±10, WT vs APP/PS1, respectively), a higher incidence of cardiac arrhythmias (events/h 6.0±1.0 vs 12±1.5, WT vs APP/PS1, respectively), and sleep-disordered breathing (AHI: 8.5±2.0 vs 18.0±3.0, WT vs APP/PS1, respectively). Partial ablation of RVLM-C1 neurons (~70%) in APP/PS1 mice resulted in a two-fold and three-fold reduction in cardiac sympathetic drive and arrhythmogenesis, respectively. Furthermore, APP/PS1 mice treated with DβH-SAP showed marked improvements in breathing regularity (IS: 7.9±1.1 vs 16.9±2.2, APP/PS1DβH-SAP vs APP/PS1, respectively) and a restoration of normal sleep effciency (SE: 75.5±4.3 vs 58.1±6.4, APP/PS1DβH-SAP vs APP/PS1, respectively) compared to untreated APP/PS1 mice. Our results show that RVLM-C1 neurons play a main role in the development/maintenance of cardiorespiratory disorders in experimental AD. FONDECYT 11220962, 1220950. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.