Interferon-γ production by Tfh cells is required for CXCR3+ pre-memory B cell differentiation and subsequent lung-resident memory B cell responses.

Lung-resident memory B cells (lung-BRMs) differentiate into plasma cells after reinfection, providing enhanced pulmonary protection. Here, we investigated the determinants of lung-BRM differentiation upon influenza infection. Kinetic analyses revealed that influenza nucleoprotein (NP)-specific BRMs preferentially differentiated early after infection and required T follicular helper (Tfh) cell help. BRM differentiation temporally coincided with transient interferon (IFN)-γ production by Tfh cells. Depletion of IFN-γ in Tfh cells prevented lung-BRM differentiation and impaired protection against heterosubtypic infection. IFN-γ was required for expression of the transcription factor T-bet by germinal center (GC) B cells, which promoted differentiation of a CXCR3+ GC B cell subset that were precursors of lung-BRMs and CXCR3+ memory B cells in the mediastinal lymph node. Absence of IFN-γ signaling or T-bet in GC B cells prevented CXCR3+ pre-memory precursor development and hampered CXCR3+ memory B cell differentiation and subsequent lung-BRM responses. Thus, Tfh-cell-derived IFN-γ is critical for lung-BRM development and pulmonary immunity, with implications for vaccination strategies targeting BRMs.

Role of endometrial sampling to differentiate between advanced endometrial versus ovarian malignancy: retrospective cohort study.

OBJECTIVE: Distinguishing between advanced stage endometrial and ovarian cancer at diagnosis can be challenging, especially when patients do not present with abnormal uterine bleeding. Given emerging systemic therapies specific for ovarian versus endometrial cancers, it has become increasingly critical to establish the correct diagnosis at presentation to ensure appropriate treatment. This study evaluates the frequency with which advanced endometrial cancer is mistakenly presumed to be ovarian cancer. METHODS: A retrospective analysis was performed of patients with a final diagnosis of advanced endometrial cancer treated consecutively at a single academic institution between 2013 and 2022. Variables abstracted included abnormal uterine bleeding, endometrial sampling, and timing of endometrial cancer diagnosis. We quantified incorrect diagnoses made after 2018, when frontline targeted treatments differentiating advanced endometrial from advanced ovarian cancer became available. RESULTS: We identified 270 patients with an ultimate diagnosis of stage III or IV endometrial cancer. The most common presenting symptom was abnormal uterine bleeding (219/270, 81%), followed by abdominal or pelvic pain (48/270, 18%) and bloating (27/270, 10%). Forty-eight patients (18%) received neoadjuvant chemotherapy, of whom 11 (23%) had an incorrect diagnosis of ovarian cancer. Since 2018, six patients have received neoadjuvant chemotherapy for presumed ovarian cancer, three of whom received a systemic regimen specific for ovarian cancer when they, in fact, had endometrial cancer. CONCLUSION: In patients with presumed advanced ovarian cancer dispositioned to neoadjuvant chemotherapy, endometrial sampling can identify some cases that are actually primary endometrial cancers. Correct diagnosis guides the use of appropriate antineoplastic therapies, optimizing response and survival outcomes while minimizing toxicity and cost of unindicated therapies.

Does acute funisitis predict worse neonatal outcomes among term newborns?

BACKGROUND: Acute funisitis-the histologic diagnosis of inflammation within the umbilical cord-represents a fetal inflammatory response to infection. Although acute funisitis has been associated with an increased risk of adverse outcomes among preterm neonates, there are limited and conflicting data with term deliveries. OBJECTIVE: This study aimed to evaluate the association between acute funisitis and neonatal morbidity in neonates born at term to pregnant patients with a clinical diagnosis of intraamniotic infection. STUDY DESIGN: This was a retrospective cohort study of pregnant patients who had clinically diagnosed intraamniotic infection at term, delivered vaginally at a single tertiary institution from 2013 to 2019, and had histologic chorioamnionitis on placental pathology. Patients with intrauterine fetal demise or missing neonatal/placental pathology data were excluded. The primary outcome was a neonatal sepsis composite, defined as culture-positive bacteremia, neutropenia (absolute neutrophil count<3500/µL), or immature-to-total neutrophil ratio>0.2. The secondary outcomes included composite neonatal morbidity, defined as neonatal intensive care unit admission, 5-minute Apgar score <7, bacteremia, endotracheal intubation or need for continuous positive airway pressure, intraventricular hemorrhage (grade 3 or 4), necrotizing enterocolitis (stage 3 or 4), umbilical artery pH<7.1, umbilical artery base excess>12, and neonatal mortality. The components of these composites, neonatal intensive care unit length of stay, and Kaiser early-onset sepsis score were also measured. Neonates with acute funisitis on pathology were compared with those without acute funisitis using bivariate statistics. Regression was used to estimate the relative risk of outcomes. RESULTS: Of 184 neonates with deliveries complicated by intraamniotic infection, acute funisitis was present in 109 (59%) placental specimens. Composite neonatal sepsis was significantly higher among neonates with acute funisitis (relative risk, 1.85; 95% confidence interval, 1.13-3.03) than in those without acute funisitis. As a marker for sepsis, acute funisitis has a sensitivity of 39.4%, negative predictive value of 47.2%, specificity of 78.7%, and positive predictive value of 72.9%. An immature-to-total neutrophil ratio>0.2 (relative risk, 1.83; 95% confidence interval, 1.09-3.08) was also significantly associated with acute funisitis. Neonatal morbidity composite, intraventricular hemorrhage, necrotizing enterocolitis, neonatal intensive care unit admission, higher Kaiser early-onset sepsis scores, and other examined outcomes were not statistically associated with acute funisitis. CONCLUSION: In term deliveries complicated by intraamniotic infection, acute funisitis was associated with increased neonatal sepsis. Current approaches for estimating neonatal sepsis risk are limited by their reliance on indirect maternal factors such as maximum maternal temperature and intrapartum antibiotic use. This study suggests that acute funisitis may serve as a marker that could be utilized to augment risk stratification at birth if a protocol for evaluating the umbilical cord in real-time were widely adopted.

Role of Small Hydrophobic Protein of J Paramyxovirus in Virulence.

J paramyxovirus (JPV) was first isolated from moribund mice with hemorrhagic lung lesions in Australia in 1972. It is a paramyxovirus classified under the newly proposed genus Jeilongvirus JPV has a genome of 18,954 nucleotides, consisting of eight genes in the order 3'-N-P/V/C-M-F-SH-TM-G-L-5'. JPV causes little cytopathic effect (CPE) in tissue culture cells but severe disease in mice. The small hydrophobic (SH) protein is an integral membrane protein encoded by many paramyxoviruses, such as mumps virus (MuV) and respiratory syncytial virus (RSV). However, the function of SH has not been defined in a suitable animal model. In this work, the functions of SH of JPV, MuV, and RSV have been examined by generating recombinant JPV lacking the SH protein (rJPV-ΔSH) or replacing SH of JPV with MuV SH (rJPV-MuVSH) or RSV SH (rJPV-RSVSH). rJPV-ΔSH, rJPV-MuVSH, and rJPV-RSVSH were viable and had no growth defect in tissue culture cells. However, more tumor necrosis factor alpha (TNF-α) was produced during rJPV-ΔSH infection, confirming the role of SH in inhibiting TNF-α production. rJPV-ΔSH induced more apoptosis in tissue culture cells than rJPV, rJPV-MuVSH, and rJPV-RSVSH, suggesting that SH plays a role in blocking apoptosis. Furthermore, rJPV-ΔSH was attenuated in mice compared to rJPV, rJPV-MuVSH, and rJPV-RSVSH, indicating that the SH protein plays an essential role in virulence. The results indicate that the functions of MuV SH and RSV SH are similar to that of JPV SH even though they have no sequence homology.IMPORTANCE Paramyxoviruses are associated with many devastating diseases in animals and humans. J paramyxovirus (JPV) was isolated from moribund mice in Australia in 1972. Newly isolated viruses, such as Beilong virus (BeiPV) and Tailam virus (TlmPV), have genome structures similar to that of JPV. A new paramyxovirus genus, Jeilongvirus, which contains JPV, BeiPV, and TlmPV, has been proposed. Small hydrophobic (SH) protein is present in many paramyxoviruses. Our present study investigates the role of SH protein of JPV in pathogenesis in its natural host. Understanding the pathogenic mechanism of Jeilongvirus is important to control and prevent potential diseases that may emerge from this group of viruses.

Maternal and peripartum risk factors for acute funisitis among term deliveries complicated by intraamniotic infection.

BACKGROUND: Acute funisitis-the histologic diagnosis of inflammation within the umbilical cord-represents a fetal inflammatory response and has been associated with adverse neonatal outcomes. Little is known regarding the maternal and intrapartum risk factors associated with the development of acute funisitis among term deliveries complicated by intraamniotic infection. OBJECTIVE: This study aimed to identify the maternal and intrapartum risk factors associated with developing acute funisitis among term deliveries complicated by intraamniotic infection. STUDY DESIGN: After institutional review board approval, we conducted a retrospective cohort study of term deliveries affected by clinical intraamniotic infection at a single tertiary center between 2013 and 2017, with placental pathology consistent with histologic chorioamnionitis. The exclusion criteria included intrauterine fetal demise, missing delivery information or placental pathology, and documented congenital fetal abnormalities. Maternal sociodemographic, antepartum, and intrapartum factors were compared among patients with acute funisitis on pathology to those without acute funisitis using bivariate statistics. Regression models were developed to estimate the adjusted odds ratios. RESULTS: Of 123 patients meeting the inclusion criteria, 75 (61%) had acute funisitis on placental pathology. Compared with placental specimens without acute funisitis, acute funisitis was observed more frequently among patients with maternal BMI ≥30 kg/m2 (58.7% vs 39.6%, P=.04) and labor courses with increased rupture of membrane duration (17.3 vs 9.6 hours, P=.001). Use of fetal scalp electrode was observed less frequently in acute funisitis (5.3% vs 16.7%, P=.04) than cases without acute funisitis. In regression models, maternal BMI ≥30 kg/m2 (adjusted odds ratio, 2.67; 95% confidence interval, 1.21-5.90) and rupture of membrane >18 hours (adjusted odds ratio, 2.48; 95% confidence interval, 1.07-5.75) were significantly associated with acute funisitis. Fetal scalp electrode use (adjusted odds ratio, 0.18; 95% confidence interval, 0.04-0.71) was negatively associated with acute funisitis. CONCLUSION: In term deliveries with intraamniotic infection and histologic chorioamnionitis, maternal BMI ≥30 kg/m2, and rupture of membrane>18 hours were associated with acute funisitis on placental pathology. As insight into the clinical impact of acute funisitis grows, the ability to predict which pregnancies are at the greatest risk for its development may allow for a tailored approach to predicting neonatal risk for sepsis and related comorbidity.

Broad Cross-Reactive IgA and IgG against Human Coronaviruses in Milk Induced by COVID-19 Vaccination and Infection.

It is currently unclear if SARS-CoV-2 infection or mRNA vaccination can also induce IgG and IgA against common human coronaviruses (HCoVs) in lactating parents. Here we prospectively analyzed human milk (HM) and blood samples from lactating parents to measure the temporal patterns of anti-SARS-CoV-2 specific and anti-HCoV cross-reactive IgA and IgG responses. Two cohorts were analyzed: a vaccination cohort (n = 30) who received mRNA-based vaccines for COVID-19 (mRNA-1273 or BNT162b2), and an infection cohort (n = 45) with COVID-19 disease. Longitudinal HM and fingerstick blood samples were collected pre- and post-vaccination or, for infected subjects, at 5 time-points 14-28 days after confirmed diagnosis. The anti-spike(S) and anti-nucleocapsid(N) IgA and IgG antibody levels against SARS-CoV-2 and HCoVs were measured by multiplex immunoassay (mPlex-CoV). We found that vaccination significantly increased the anti-S IgA and IgG levels in HM. In contrast, while IgG levels increased after a second vaccine dose, blood and HM IgA started to decrease. Moreover, HM and blood anti-S IgG levels were significantly correlated, but anti-S IgA levels were not. SARS2 acute infection elicited anti-S IgG and IgA that showed much higher correlations between HM and blood compared to vaccination. Vaccination and infection were able to significantly increase the broadly cross-reactive IgG recognizing HCoVs in HM and blood than the IgA antibodies in HM and blood. In addition, the broader cross-reactivity of IgG in HM versus blood indicates that COVID-19 vaccination and infection might provide passive immunity through HM for the breastfed infants not only against SARS-CoV-2 but also against common cold coronaviruses.

Broad Cross-reactive IgA and IgG Against Human Coronaviruses in Milk Induced by COVID-19 Vaccination and Infection.

It is currently unclear if SARS-CoV-2 infection or mRNA vaccination can also induce IgG and IgA against common human coronaviruses (HCoVs) in lactating parents. Here we prospectively analyzed human milk (HM) and blood samples from lactating parents to measure the temporal patterns of anti-SARS-CoV-2 specific and anti-HCoV cross-reactive IgA and IgG responses. Two cohorts were analyzed: a vaccination cohort (n=30) who received mRNA-based vaccines for COVID-19 (mRNA-1273 or BNT162b2), and an infection cohort (n=45) with COVID-19 disease. Longitudinal HM and fingerstick blood samples were collected pre- and post-vaccination or, for infected subjects, at 5 time-points 14 - 28 days after confirmed diagnosis. The anti-spike(S) and antinucleocapsid(N) IgA and IgG antibody levels against SARS-CoV-2 and HCoVs were measured by multiplex immunoassay (mPlex-CoV). We found that vaccination significantly increased the anti-S IgA and IgG levels in HM. In contrast, while IgG levels increased after a second vaccine dose, blood and HM IgA started to decrease. Moreover, HM and blood anti-S IgG levels were significantly correlated, but anti-S IgA levels were not. SARS2 acute infection elicited anti-S IgG and IgA that showed much higher correlations between HM and blood compared to vaccination. Vaccination and infection were able to significantly increase the broadly cross-reactive IgG recognizing HCoVs in HM and blood than the IgA antibodies in HM and blood. In addition, the broader cross-reactivity of IgG in HM versus blood indicates that COVID-19 vaccination and infection might provide passive immunity through HM for the breastfed infants not only against SARS-CoV-2 but also against common cold coronaviruses. IMPORTANCE: It is unknown if COVID-19 mRNA vaccination and infection in lactating mothers results in cross-reactive antibodies against other common human coronaviruses. Our study demonstrates that mRNA vaccination and COVID-19 infection increase anti-spike SARS-CoV-2 IgA and IgG in both blood and milk. IgA and IgG antibody concentrations in milk were more tightly correlated with concentrations in blood after infection compared to mRNA vaccination. Notably, both infection and vaccination resulted in increased IgG against common seasonal ß -coronaviruses. This suggests that SARS-CoV-2 vaccination or infection in a lactating parent may result in passive immunity against SARS-CoV-2 and seasonal coronaviruses for the recipient infant.

Associations of Healthcare Affordability, Availability, and Accessibility with Quality Treatment Metrics in Patients with Ovarian Cancer.

BACKGROUND: Differential access to quality care is associated with racial disparities in ovarian cancer survival. Few studies have examined the association of multiple healthcare access (HCA) dimensions with racial disparities in quality treatment metrics, that is, primary debulking surgery performed by a gynecologic oncologist and initiation of guideline-recommended systemic therapy. METHODS: We analyzed data for patients with ovarian cancer diagnosed from 2008 to 2015 in the Surveillance, Epidemiology, and End Results-Medicare database. We defined HCA dimensions as affordability, availability, and accessibility. Modified Poisson regressions with sandwich error estimation were used to estimate the relative risk (RR) for quality treatment. RESULTS: The study cohort was 7% NH-Black, 6% Hispanic, and 87% NH-White. Overall, 29% of patients received surgery and 68% initiated systemic therapy. After adjusting for clinical variables, NH-Black patients were less likely to receive surgery [RR, 0.83; 95% confidence interval (CI), 0.70-0.98]; the observed association was attenuated after adjusting for healthcare affordability, accessibility, and availability (RR, 0.91; 95% CI, 0.77-1.08). Dual enrollment in Medicaid and Medicare compared with Medicare only was associated with lower likelihood of receiving surgery (RR, 0.86; 95% CI, 0.76-0.97) and systemic therapy (RR, 0.94; 95% CI, 0.92-0.97). Receiving treatment at a facility in the highest quartile of ovarian cancer surgical volume was associated with higher likelihood of surgery (RR, 1.12; 95% CI, 1.04-1.21). CONCLUSIONS: Racial differences were observed in ovarian cancer treatment quality and were partly explained by multiple HCA dimensions. IMPACT: Strategies to mitigate racial disparities in ovarian cancer treatment quality must focus on multiple HCA dimensions. Additional dimensions, acceptability and accommodation, may also be key to addressing disparities.

Capsule Promotes Intracellular Survival and Vascular Endothelial Cell Translocation during Invasive Pneumococcal Disease.

The polysaccharide capsule that surrounds Streptococcus pneumoniae (Spn) is one of its most important virulence determinants, serving to protect against phagocytosis. To date, 100 biochemical and antigenically distinct capsule types, i.e., serotypes, of Spn have been identified. Yet how capsule influences pneumococcal translocation across vascular endothelial cells (VEC), a key step in the progression of invasive disease, was unknown. Here, we show that despite capsule being inhibitory of Spn uptake by VEC, capsule enhances the escape rate of internalized pneumococci and thereby promotes translocation. Upon investigation, we determined that capsule protected Spn against intracellular killing by VEC and H2O2-mediated killing in vitro. Using a nitroblue tetrazolium reduction assay and nuclear magnetic resonance (NMR) analyses, purified capsule was confirmed as having antioxidant properties which varied according to serotype. Using an 11-member panel of isogenic capsule-switch mutants, we determined that serotype affected levels of Spn resistance to H2O2-mediated killing in vitro, with killing resistance correlated positively with survival duration within VEC, rate of transcytosis to the basolateral surface, and human attack rates. Experiments with mice supported our in vitro findings, with Spn producing oxidative-stress-resistant type 4 capsule being more organ-invasive than that producing oxidative-stress-sensitive type 2 capsule during bacteremia. Capsule-mediated protection against intracellular killing was also observed for Streptococcus pyogenes and Staphylococcus aureus. We conclude that capsular polysaccharide plays an important role within VEC, serving as an intracellular antioxidant, and that serotype-dependent differences in antioxidant capabilities impact the efficiency of VEC translocation and a serotype's potential for invasive disease. IMPORTANCE Streptococcus pneumoniae (Spn) is the leading cause of invasive disease. Importantly, only a subset of the 100 capsule types carried by Spn cause the majority of serious infections, suggesting that the biochemical properties of capsular polysaccharide are directly tied to virulence. Here, we describe a new function for Spn's capsule-conferring resistance to oxidative stress. Moreover, we demonstrate that capsule promotes intracellular survival of pneumococci within vascular endothelial cells and thereby enhances bacterial translocation across the vasculature and into organs. Using isogenic capsule-switch mutants, we show that different capsule types, i.e., serotypes, vary in their resistance to oxidative stress-mediated killing and that resistance is positively correlated with intracellular survival in an in vitro model, organ invasion during bacteremia in vivo, and epidemiologically established pneumococcal attack rates in humans. Our findings define a new role of capsule and provide an explanation for why certain serotypes of Spn more frequently cause invasive pneumococcal disease.

Parents, Peers, and Musical Play: Integrated Parent-Child Music Class Program Supports Community Participation and Well-Being for Families of Children With and Without Autism Spectrum Disorder.

Opportunities for meaningful community participation may influence the development and well-being of individuals with autism spectrum disorder (ASD) and their families as well as impact how community members perceive and understand ASD. In the current study, we aimed to understand how a parent-child integrated music class program could be used to promote community participation and family well-being. Caregivers of preschoolers (2-5 years of age) with ASD and those of peer children with typical development (TD) were interviewed about their participation in a parent-child integrated music class program. Thematic analysis of interviews revealed that all caregivers viewed program participation as positive. Caregivers emphasized increasing connections within families, such as through strengthening parent-child bonds, as well as connections across families, including increased understanding of ASD and sensitivity to the experience of parenting. Many caregivers perceived the class as supporting their parenting and impacting their children's behavior in meaningful ways. Interview themes were supported by measures of caregiver and child program receipt, including questionnaires about family music engagement throughout their time in the class program and behavioral coding of children's engagement during music classes. Findings suggest that integrated community experiences such as parent-child music classes may impact whole family well-being, highlighting the value of integrated community participation experiences at the level of the family system. Parent-child music classes may provide a productive and accessible context for supporting integrated community experiences.

Dog overpopulation and diagnosis of intestinal parasites on Santa Cruz Island, Galapagos 2016.

Dog overpopulation and diseases are hazards to native island species and humans on the Galapagos. The main objective of the study reported here was to estimate the observed human:dog ratio on Santa Cruz Island, Galapagos in September 2016. In addition, dog demographic data were used to model the expected annual dog population growth in the next 10 years. A secondary objective was to measure the burden of dogs infected with intestinal parasites. The observed human:dog ratio was 964:202 (or 4.77:1), which extrapolates to 3290 dogs; an increase of 31% in the dog population on Santa Cruz from 2014 to 2016. Study results show that current spay-neuter efforts (about 300 dogs per year; 60% females, 40% males) are not enough to keep the population stable (i.e., current baseline of 3290 dogs). The frequency of dogs infected with Ancylostoma spp., an intestinal parasite in dogs that can cause cutaneous larval migrans in humans, was 18/44 or 41% (95% CI = 27%, 55%). These results provide the most complete assessment of the dog overpopulation on the Galapagos to date.

Lichen planus pemphigoides associated with pregnancy mimicking pemphigoid gestationis.

Lichen planus pemphigoides (LPP) is a rare condition characterized by tense blisters that arise on lesions of lichen planus (LP) and on unaffected skin. We present the case of a 25-year-old pregnant woman at 12 weeks' gestation who developed an acute bullous eruption after 5 months of worsening LP. Similarities to pemphigoid gestationis (PG) included lesions around the periumbilical area and multiple urticarial erythematous papules and plaques in addition to linear C3 and IgM deposition along the basement membrane zone (BMZ) on direct immunofluorescence (DIF).

Dog overpopulation and burden of exposure to canine distemper virus and other pathogens on Santa Cruz Island, Galapagos.

Dog overpopulation and diseases are hazards to native island species and humans on the Galapagos. Vaccination and importation of dogs are prohibited on the Galapagos. Risk management of these hazards requires the use of science-based risk assessment and risk communication. The objectives of the study reported here were (i) to estimate the human:dog ratio and (ii) the prevalence of and identify exposure factors associated with positive antibody titers to canine distemper virus (CDV) and other pathogens, as well as infection with intestinal parasites in owned dogs on Santa Cruz Island, Galapagos in September 2014. The observed human:dog ratio was 6.148:1 which extrapolates to 2503 dogs (two times more than a recent dog count conducted by Galapagos Biosecurity Agency in March 2014). The proportion of spayed female dogs (50%) was higher, compared to neutered male dogs (30%) (p=0.04). Prevalence of dogs with positive antibody titers to CDV was 36% (95% CI=26, 46%), to canine parvovirus was 89% (95% CI=82, 95%), and to canine adenovirus was 40% (95% CI=30, 51%). The frequency of seropositive dogs to CDV was lower in urban dogs (26%), compared to rural dogs (53%) (p<0.05). A positive interaction effect between rural residence and spay/neuter status on seropositivity to CDV was observed, which we discuss in this report. Because vaccination is prohibited, the dog population on Santa Cruz is susceptible to an outbreak of CDV (particularly among urban dogs) with potential spill over to marine mammals. Dog's age (1-2 or 3-14 years old, compared to younger dogs), and residence (rural, urban) were associated with positive antibody titers to parvovirus, adenovirus, Ehrlichia spp., or Anaplasma spp., as well as infection with Ancylostoma spp., an intestinal parasite in dogs that can be transmitted to humans, particularly children. These results provide the most comprehensive assessment of dog overpopulation and exposure to CDV and other pathogens on the Galapagos to date.

In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the beta-amyloid depositing mice.

The metabolism of the amyloid precursor protein (APP) and tau are central to the pathobiology of Alzheimer's disease (AD). We have examined the in vivo turnover of APP, secreted APP (sAPP), Abeta and tau in the wild-type and Tg2576 mouse brain using cycloheximide to block protein synthesis. In spite of overexpression of APP in the Tg2576 mouse, APP is rapidly degraded, similar to the rapid turnover of the endogenous protein in the wild-type mouse. sAPP is cleared from the brain more slowly, particularly in the Tg2576 model where the half-life of both the endogenous murine and transgene-derived human sAPP is nearly doubled compared to wild-type mice. The important Abeta degrading enzymes neprilysin and IDE were found to be highly stable in the brain, and soluble Abeta40 and Abeta42 levels in both wild-type and Tg2576 mice rapidly declined following the depletion of APP. The cytoskeletal-associated protein tau was found to be highly stable in both wild-type and Tg2576 mice. Our findings unexpectedly show that of these various AD-relevant protein metabolites, sAPP turnover in the brain is the most different when comparing a wild-type mouse and a beta-amyloid depositing, APP overexpressing transgenic model. Given the neurotrophic roles attributed to sAPP, the enhanced stability of sAPP in the beta-amyloid depositing Tg2576 mice may represent a neuroprotective response.