Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy.

Extracellular deposition of amyloid-ß as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer's disease1,2. The regional progression of brain atrophy in Alzheimer's disease highly correlates with tau accumulation but not amyloid deposition3-5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-ß or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer's disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer's disease and primary tauopathies.

Adherence to physical activity recommendations and barriers to physical activity participation among adults with type 1 diabetes.

BACKGROUND: Physical activity (PA) is important for those with type 1 diabetes (T1DM); however, accurate information on PA in people with T1DM is limited. AIMS: This study assessed adherence to PA guidelines using both objective and subjective PA measures and evaluated the relationship between accelerometer-measured PA and cardiovascular disease (CVD) risk factors. Barriers to PA were also assessed. METHODS: Using an observational cross-sectional design, PA was measured objectively over 7 days in 72 participants (34 males) using an accelerometer (ActiGraph) and subjectively using the International Physical Activity Questionnaire (IPAQ). Perceived barriers to PA were assessed using the Barriers to Physical Activity in Diabetes (type 1) scale. Multiple linear regression models assessed the influence of PA on HbA1c and CVD risk factors. RESULTS: Mean age ± SD was 40.9 ± 12.9 years, diabetes duration was 18 ± 11.6 years, and HbA1c was 65 ± 14 mmol/mol /8.0 ± 1.3%. Twenty-three (32%) participants exercised according to PA recommendations as measured by an accelerometer. Sixty-nine (97%) participants reported meeting the recommendations as per the IPAQ. Those meeting recommendations (accelerometry) had a lower HbA1c (p = 0.001), BMI (p = 0.032), waist circumference (p = 0.006), and fat mass (p = 0.032) and a greater number of hypoglycaemic events (p = 0.004). Fear of hypoglycaemia was the strongest barrier to PA (mean 3.4 ± 2.0). CONCLUSION: The majority of participants failed to meet PA recommendations. Meeting the recommendations was associated with healthier CVD risk factor profiles. Individuals with T1DM possibly overestimate their PA using self-reported measures and require support and education to safely improve activity levels.

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model.

OBJECTIVE: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-ß deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. METHODS: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. RESULTS: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. INTERPRETATION: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952-966.

Coercive Control in Intimate Relationships: Differences Across Age and Sex.

Research indicates that intimate partner violence (IPV) victimization is a gendered phenomenon with a plethora of studies exploring the relationship between sex and IPV experiences. The literature, however, has primarily focused on IPV among young couples with limited attention to how abuse manifests and changes as individuals grow old. In particular, studies have not fully analyzed how coercive control experiences vary across age, as well as by sex. The current study expands upon prior work using data from the National Intimate Partner and Sexual Violence Survey (NISVS) to investigate how the effects of sex on two forms of coercive control, intimidation and surveillance, are moderated by age, while controlling for health impairment and other key demographic characteristics. The findings reveal that older persons regardless of gender are less likely to experience surveillance or intimidation. However, men compared with women are significantly more likely to report surveillance, and younger women are significantly more likely to report experiencing intimidation compared with younger men. Implications and directions for future research are presented.

Lack of hepatic apoE does not influence early Aß deposition: observations from a new APOE knock-in model.

BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-ß (Aß) deposition in the brain in the form of both Aß-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. METHODS: We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. RESULTS: As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aß accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. CONCLUSIONS: Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

Malaria Prophylaxis Adherence Among Aircrew Members.

INTRODUCTION: Joint Base Charleston's C-17 Globemaster III mission is executed by 400 active-duty members from three operational and support wings. Aircrew and mission-essential personnel travel to locations with endemic diseases which are mostly eradicated in the United States. Recently, two members contracted malaria after missions in Africa which required advanced hospital care. Personnel were provided chemoprophylaxis, but the members who contracted malaria were among several who chose not to take it. This preliminary survey assessed aircrew malaria prophylaxis adherence and examined potential factors contributing to nonadherence.METHODS: JB Charleston aircrew members who visited the Flight and Operational Medicine Clinic between January and April 2018 were administered a retrospective, online survey. Researchers performed descriptive statistics and Chi-squared analysis.RESULTS: Most respondents were pilots under 30 yr of age and were prescribed malaria chemoprophylaxis while on a mission. More than two-thirds of respondent aircrew members did not take the medication as prescribed or did not take it at all. Of those, over half of respondents stated too many pills/too many days and medication side effects as the main reasons for nonadherence. Furthermore, almost 70% of adherent members experienced negative medication side effects such as nausea and heightened dreams. There was no statistical relationship between crew position, age, side effects, and prophylaxis adherence.DISCUSSION: Numerous factors contribute to poor prophylaxis regimen compliance among aircrew members. This study highlighted the need for risk-based policy validation, improved patient education, prophylaxis enforcement, process improvements to facilitate adherence, and evaluation of perceived vs. actual risk.Rutherford AE, Yale RS, Finn MF. Malaria prophylaxis adherence among aircrew members. Aerosp Med Hum Perform. 2019; 90(7):643-646.

The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans.

The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of ß-amyloid (Aß) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aß plaques. However, tau, not Aß, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aß and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

Obstructive sleep apnea treatment, slow wave activity, and amyloid-ß.

Obstructive sleep apnea (OSA) increases risk of dementia, a relationship that may be mediated by amyloid-ß (Aß) and downstream Alzheimer disease pathology. We previously showed that OSA may impair Aß clearance and affect the relationship between slow wave activity (SWA) and Aß. In this study, SWA and CSF Aß were measured in participants with OSA before and 1 to 4 months after treatment. OSA treatment increased SWA, and SWA was significantly correlated with lower Aß after treatment. Greater improvement in OSA was associated with greater decreases in Aß. We propose a model whereby OSA treatment may affect both Aß release and clearance. Ann Neurol 2018 ANN NEUROL 2019;85:291-295.

Defining and Predicting Pimps' Coerciveness Toward Sex Workers: Socialization Processes.

Prior research has found that pimps use both non-coercive and coercive management styles across and within market segments of the illicit sex trade. The current study is the first to examine the socialization processes underlying variation in the self-reported coerciveness of pimps. This study begins to fill a void in the almost non-existent research on pimps who are actively managing Internet-solicited sex workers, and adds to the sparse research on pimps' coerciveness. We extend Anderson's concepts of "street code" families, where respect is acquired through displaying physical violence and toughness, and "decent" families, where middle class values of avoiding unnecessary aggression and complying with the law prevail, to understand variation in the degree of coerciveness that pimps utilize toward sex workers. A purposive sample of 44 active pimps was obtained through referrals from selected pimps and through placing advertisements on Backpage, a website utilized by the illicit prostitution trade. Qualitative coding revealed a wide range of coercive control tactics such as supplying drugs, surveillance, and physical violence. Pimps who served as sex workers and those raised by parents who supported "the code of the street" reported use of a greater number of more severe coercive tactics. College-educated pimps, pimps operating business that charged fees of at least US$300, and those from "decent" families were more likely to use non-coercive management. These findings suggest that early prevention programs might address the "street code" mentality that contributes to coerciveness, and that "End Demand" policies need to recognize that many male pimps also have served as sex workers.

Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation.

The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid ß (Aß) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aß pathology in mice producing both human Aß and apoE4, and investigated the mechanism underlying these effects. We utilized APPPS1-21 mice crossed to apoE4-knockin mice expressing human apoE4 (APPPS1-21/APOE4). We discovered an anti-human apoE antibody, anti-human apoE 4 (HAE-4), that specifically recognizes human apoE4 and apoE3 and preferentially binds nonlipidated, aggregated apoE over the lipidated apoE found in circulation. HAE-4 also binds to apoE in amyloid plaques in unfixed brain sections and in living APPPS1-21/APOE4 mice. When delivered centrally or by peripheral injection, HAE-4 reduced Aß deposition in APPPS1-21/APOE4 mice. Using adeno-associated virus to express 2 different full-length anti-apoE antibodies in the brain, we found that HAE antibodies decreased amyloid accumulation, which was dependent on Fcγ receptor function. These data support the hypothesis that a primary mechanism for apoE-mediated plaque formation may be a result of apoE aggregation, as preferentially targeting apoE aggregates with therapeutic antibodies reduces Aß pathology and may represent a selective approach to treat AD.

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of ß-amyloidosis.

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aß pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aß pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in Aß plaque size and a reduction in plaque-associated neuritic dystrophy with no change in overall plaque load. These results suggest that lowering apoE levels prior to plaque deposition can strongly affect the initiation of Aß pathology while lowering apoE after Aß seeding modulates plaque size and toxicity.

TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer's disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found TREM2 is protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglial signaling and are deleterious. However, the potential role of TREM2 in the context of tau pathology has not yet been characterized. In this study, we crossed Trem2+/+ (T2+/+) and Trem2-/- (T2-/-) mice to the PS19 human tau transgenic line (PS) to investigate whether loss of TREM2 function affected tau pathology, the microglial response to tau pathology, or neurodegeneration. Strikingly, by 9 mo of age, T2-/-PS mice exhibited significantly less brain atrophy as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared with T2+/+PS mice. However, no TREM2-dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2-/-PS mice exhibited significantly reduced microgliosis in the hippocampus and piriform cortex compared with T2+/+PS mice. Gene expression analyses and immunostaining revealed microglial activation was significantly attenuated in T2-/-PS mice, and there were lower levels of inflammatory cytokines and astrogliosis. These unexpected findings suggest that impairing microglial TREM2 signaling reduces neuroinflammation and is protective against neurodegeneration in the setting of pure tauopathy.

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-ß pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-ß pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-ß pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Subtle radiographic signs of hamate body fracture: a diagnosis not to miss in the emergency department.

Hamate fractures are estimated to represent 1.7% of all carpal fractures and can occur at the hamulus (hook) or hamate body depending on mechanism of injury. Fractures of the hamate body can be exceedingly difficult to identify on standard wrist and hand radiographs in the emergency department. If the diagnosis is missed in the emergency department, orthopedic referral is often delayed. This can result in lasting functional disability for the patient, as these fractures have a propensity to destabilize the fourth and fifth carpometacarpal (CMC) joints. In this pictorial essay, we present six radiographic signs indicative of hamate body fracture with computed tomography (CT) imaging correlation. Injury mechanism and fracture classification schemes are portrayed to aid in the understanding of these injuries. Once radiographs raise suspicion for a hamate body fracture, further characterization with CT and orthopedic referral is paramount. Goals of orthopedic management include reestablishment of the fourth and fifth CMC articular surface, stabilization of the CMC joints, and appropriate treatment of concomitant soft tissue injury.

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy.

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain.

Coercive Control and Physical Violence in Older Adults: Analysis Using Data From the National Elder Mistreatment Study.

The most common perpetrators of physical violence against women of any age are their intimate partners. Although research on younger adults has recognized that intimate partner violence (IPV) is distinct in etiology, form, and consequence, whether the same is true for older adults has not been adequately studied. The extent and consequences of coercive controlling violence, IPV that involves physical violence coupled with psychological aggression and/or financial abuse, have not been examined in older populations. Using data from the National Elder Mistreatment Study, the current research examines if coercive control is more evident in physical violent victimizations of older adults (age 60 or older) when the perpetrator is an intimate partner compared with when the perpetrator is not an intimate partner. Findings indicate that older adults who experience emotional coercive control by intimate partners in their lifetime are more likely to experience physical abuse at age 60 or older. Furthermore, older adults who experienced trauma during their lifetime, were in poor health, and with less social support are more likely to experience physical abuse at age 60 or older. However, the victim's sex had no significant influence on the likelihood of experiencing physical abuse.

Estimating diesel fuel exposure for a plumber repairing an underground pipe.

We estimated the diesel fuel exposure of a plumber repairing an underground water line leak at a truck stop. The repair work was performed over three days during which the plumber spent most of his time in a pit filled with a mixture of water and diesel fuel. Thus, the plumber was exposed via both the inhalation and dermal routes. While previously asymptomatic, he was diagnosed with acute renal failure 35 days after working at this site. No measurements were available for estimating either inhalation or dermal exposures or the cumulative dose and, therefore, two different approaches were used that were based on simple models of the exposure scenario. The first approach used the ideal gas law with the vapor pressure of the diesel fuel mixture to estimate a saturation vapor concentration, while the second one used a mass balance of the petroleum hydrocarbon component of diesel fuel in conjunction with the Henry's Law constant for this mixture. These inhalation exposure estimates were then adjusted to account for the limited ventilation in a confined space. The inhalation exposure concentrations predicted when handling the water layer alone is much lower than that expected from the organic layer. This case study illustrates the large differences in inhalation exposure associated with volatile organic layers and aqueous solution containing these chemicals. The estimate of dermal exposure was negligible compared to the inhalation exposure because the skin presents a much smaller surface area of exposure to the contaminant compared to the lungs. The methodology presented here is useful for situations where little information is available for more formal mathematical exposure modeling, but where adjustments to the worst-case exposures, estimated simply, can provide reasonable exposure estimates.

Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid.

We hypothesized that one mechanism underlying the association between obstructive sleep apnea (OSA) and Alzheimer's disease is OSA leading to decreased slow wave activity (SWA), increased synaptic activity, decreased glymphatic clearance, and increased amyloid-ß. Polysomnography and lumbar puncture were performed in OSA and control groups. SWA negatively correlated with cerebrospinal fluid (CSF) amyloid-ß-40 among controls and was decreased in the OSA group. Unexpectedly, amyloid-ß-40 was decreased in the OSA group. Other neuronally derived proteins, but not total protein, were also decreased in the OSA group, suggesting that OSA may affect the interaction between interstitial and cerebrospinal fluid. Ann Neurol 2016;80:154-159.

Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease.

Age-related aggregation of amyloid-ß (Aß) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aß aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aß pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aß pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aß pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aß pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aß pathology in the brain.

Altered microglial response to Aß plaques in APPPS1-21 mice heterozygous for TREM2.

BACKGROUND: Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer's disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer's disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer's disease, we tested whether loss of one functional trem2 allele would affect Aß plaque deposition or the microglial response to Aß pathology in APPPS1-21 mice. RESULTS: There was no significant difference in Aß deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2+/- vs. TREM2+/+ mice. CONCLUSIONS: Loss of a single copy of trem2 had no effect on Aß pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aß deposition but that a 50% decrease inTREM2 expression does not affect Aß plaque burden.