Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model.

Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (Abeta) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA.

Estrogen therapy fails to alter amyloid deposition in the PDAPP model of Alzheimer's disease.

Epidemiological studies implicate estrogen deprivation as a risk factor for Alzheimer's disease and postmenopausal estrogen replacement as protective factor. One potential mechanism involves estrogen attenuation of beta-amyloid (Abeta) peptide accumulation. We examined the effect of estrogen on amyloid accumulation in female PDAPP mice, which express human amyloid precursor protein (APP) with the V717F mutation.

Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice.

Neuritic plaques are a defining feature of Alzheimer disease (AD) pathology. These structures are composed of extracellular accumulations of amyloid-beta peptide (Abeta) and other plaque-associated proteins, surrounded by large, swollen axons and dendrites (dystrophic neurites) and activated glia. Dystrophic neurites are thought to disrupt neuronal function, but whether this damage is static, dynamic, or reversible is unknown.

Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta.

Passive immunization with an antibody directed against the N terminus of amyloid beta (Abeta) has recently been reported to exacerbate cerebral amyloid angiopathy (CAA)-related microhemorrhage in a transgenic animal model. Although the mechanism responsible for the deleterious interaction is unclear, a direct binding event may be required. We characterized the binding properties of several monoclonal anti-Abeta antibodies to deposited Abeta in brain parenchyma and CAA.

Apolipoprotein is required for the formation of filamentous amyloid, but not for amorphous Abeta deposition, in an AbetaPP/PS double transgenic mouse model of Alzheimer's disease.

To determine the role of apolipoprotein E (apoE) in the deposition of different forms of Alzheimer amyloid deposit, we studied mice expressing both mutant human amyloid beta-protein precursor (AbetaPP) and presenilin 1 (PS1) that, in addition, were either normal or knocked-out for apoE. By 7 months of age, extensive deposits of amorphous amyloid beta (Abeta) had developed equally in both lines, indicating that, when present in high amounts, Abeta alone is sufficient for such deposition to occur. In contrast, filamentous, thioflavine S-positive amyloid deposition in AbetaPP/PS mice was catalyzed at least 3000 fold by apoE.

ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis.

Epidemiological studies suggest links between cholesterol metabolism and Alzheimer's disease (AD), with hypercholesterolemia associated with increased AD risk, and use of cholesterol-lowering drugs associated with decreased risk. Animal models using cholesterol-modifying dietary or pharmacological interventions demonstrate similar findings. Proposed mechanisms include effects of cholesterol on the metabolism of amyloid-beta (Abeta), the protein that deposits in AD brain.

Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation.

Biochemical and genetic studies indicate that the inflammatory proteins, apolipoprotein E (ApoE) and alpha(1)-antichymotrypsin (ACT) are important in the pathogenesis of Alzheimer's disease (AD). Using several lines of multiply transgenic/knockout mice we show here that murine ApoE and human ACT separately and synergistically facilitate both diffuse A beta immunoreactive and fibrillar amyloid deposition and thus also promote cognitive impairment in aged PDAPP(V717F) mice. The degree of cognitive impairment is highly correlated with the ApoE- and ACT-dependent hippocampal amyloid burden, with PDAPP mice lacking ApoE and ACT having little amyloid and little learning disability.

Use of multimetric statistical analysis to characterize and discriminate between the performance of four Alzheimer's transgenic mouse lines differing in Abeta deposition.

Behavioral assessment of genetically-manipulated mouse lines for Alzheimer's disease has become an important index for determining the efficacy of therapeutic interventions and examining disease pathogenesis. However, the potential for higher level statistical analyses to assist in these goals remains largely unexplored. The present study thus involved multimetric statistical analyses of behavioral and beta-amyloid (Abeta) deposition measures from four PDAPP-derived transgenic mouse lines that differ in extent of Abeta deposition.

Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides.

We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-beta peptides (Abeta) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Abeta, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe(-/-) astrocytes do not degrade Abeta present in Abeta plaque-bearing brain sections in vitro.

Effects of neonatal oxytocin manipulations on male reproductive potential in prairie voles.

Oxytocin (OT) modulates adult mammalian sexual behavior, sperm production and transport, and steroidogenesis; however, the consequences of developmental manipulations of oxytocin have received little attention. The purpose of this experiment was to determine whether neonatal exposure to OT, an oxytocin antagonist (OTA), saline (SAL), or handling (HAN)-only would have long-term effects on reproductive potential in male prairie voles (Microtus ochrogaster). Adult males were observed for 24 h with a sexually receptive female and sexual behavior was recorded.

Both oxytocin and vasopressin may influence alloparental behavior in male prairie voles.

Neuropeptides, especially oxytocin (OT) and arginine vasopressin (AVP), have been implicated in several features of monogamy including alloparenting. The purpose of the present study was to examine the role of OT and AVP in alloparental behavior in reproductively naïve male prairie voles. Males received intracerebroventricular (ICV) injections of artificial cerebrospinal fluid (aCSF), OT, an OT receptor antagonist (OTA), AVP, an AVP receptor antagonist (AVPA), or combinations of OTA and AVPA and were subsequently tested for parental behavior.

Sex differences and developmental effects of manipulations of oxytocin on alloparenting and anxiety in prairie voles.

In adult animals, peptide hormones, including oxytocin and arginine vasopressin, have been implicated in both parental behavior and the modulation of anxiety. The purpose of this study was to examine the consequences of developmental manipulations of oxytocin for the later expression of alloparental behavior as well as behavioral responses to a novel environment, the elevated plus maze (EPM). Prairie voles (Microtus ochrogaster), a cooperatively breeding species, were selected for this study.

Apolipoprotein E, amyloid, and Alzheimer disease.

Despite important inroads into the molecular pathology of Alzheimer disease, effective long-term treatment for the condition remains elusive. Among the many gene products that are recognized as factors in the disease is apolipoprotein ( (apoE). The risk that specific isoforms of apoE pose with regard to Alzheimer Disease clearly varies, and so the roles that apoE plays in the brain will be crucial to a full understanding of the disease and to efforts to develop effective therapies.

Relations among birth condition, maternal condition, and postnatal growth in captive common marmoset monkeys (Callithrix jacchus).

The present study characterizes the relations among maternal condition, litter size, birth condition, and growth in body weight for a population of common marmosets. The subjects of the study were marmosets born into a single colony between 1994 and 2001. Three sets of analyses were conducted to answer the following questions: 1) Is there a relationship between litter size, maternal condition, and birth condition? In the study population, maternal body weight, maternal age, litter size, and birth condition were related in a complex fashion.

ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo.

Apolipoprotein E (apoE) and clusterin can influence structure, toxicity, and accumulation of the amyloid-beta (Abeta) peptide in brain. Both molecules may also be involved in Abeta metabolism prior to its deposition. To assess this possibility, we compared PDAPP transgenic mice that develop age-dependent Abeta accumulation in the absence of apoE or clusterin as well as in the absence of both proteins.

Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein.

Amyloid-beta peptide (Abeta) is central to the pathogenesis of Alzheimer's disease, and the low-density lipoprotein receptor-related protein (LRP) has been shown to alter Abeta metabolism in vitro. Here, we show that overexpression of a functional LRP minireceptor in the brain of PDAPP mice results in age-dependent increase of soluble brain Abeta, with no changes in Abeta plaque burden. Importantly, soluble brain Abeta was found to be primarily in the form of monomers/dimers and to be highly correlated with deficits in spatial learning and memory.

A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes.

Apolipoprotein E (apoE) is an important protein involved in lipoprotein clearance and cholesterol redistribution. ApoE is abundantly expressed in astrocytes in the brain and is closely linked to the pathogenesis of Alzheimer's disease (AD). We report here that small molecule ligands that activate either liver X receptors (LXR) or retinoid X receptor (RXR) lead to a dramatic increase in apoE mRNA and protein expression as well as secretion of apoE in a human astrocytoma cell line (CCF-STTG1 cells).

Use of YFP to study amyloid-beta associated neurite alterations in live brain slices.

Neuritic plaques are one of the defining neuropathological features of Alzheimer's disease (AD). These structures are composed of a buildup of fibrils of the amyloid-beta (Abeta) peptide (amyloid) surrounded by activated glial cells and degenerating nerve processes (dystrophic neurites). To study neuritic plaques and possible abnormalities associated with dendrites, axons, and synaptic structures, we have developed an acute slice preparation model using PDAPP, yellow fluorescent protein (YFP) double transgenic mice (a mouse model with AD-like pathology that stably expresses YFP in a subset of neurons in the brain).

Sex differences and developmental effects of oxytocin on aggression and social behavior in prairie voles (Microtus ochrogaster).

Various hormones, including sex steroids and neuropeptides, have been implicated in aggression. In this study we examined (1) sex differences in intrasexual aggression in naïve prairie voles; (2) the effects of developmental manipulations of oxytocin on intrasexual aggression; and (3) changes in patterns of intrasexual aggression after brief exposure to an animal of the opposite sex. Within 24 h of birth, infants were randomly assigned to receive either an injection of oxytocin (OT) or oxytocin antagonist (OTA) or to one of two control (CTL) groups receiving either isotonic saline or handling without injection.

In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life.

Soluble amyloid-beta (Abeta) peptide converts to structures with high beta-sheet content in Alzheimer's disease (AD). Soluble Abeta is released by neurons into the brain interstitial fluid (ISF), in which it can convert into toxic aggregates. Because assessment of ISF Abeta levels may provide unique insights into Abeta metabolism and AD, an in vivo microdialysis technique was developed to measure it.

Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice.

Cerebral amyloid angiopathy (CAA) is a common cause of brain hemorrhage in the elderly. It is found in the majority of patients with Alzheimer's disease (AD). The most common form of CAA is characterized by the deposition of the amyloid-beta (Abeta) peptide in the walls of cerebral vessels, and this deposition can lead to hemorrhage and infarction.

Developmental exposure to oxytocin facilitates partner preferences in male prairie voles (Microtus ochrogaster).

The authors investigated the effects of postnatal manipulations of oxytocin (OT) on the subsequent tendency to form a partner preference in male prairie voles (Microtus ochrogaster). Neonatally, males received either an injection of OT, an oxytocin antagonist (OTA), 0.9% saline vehicle, or handling without injection.

Does my mouse have Alzheimer's disease?

Small animal models that manifest many of the characteristic neuropathological and behavioral features of Alzheimer's disease (AD) have been developed and have proven of great value for studying the pathogenesis of this disorder at the molecular, cellular and behavioral levels. The great progress made in our understanding of the genetic factors that either cause or contribute to the risk of developing AD has prompted many laboratories to create transgenic (tg) mice that overexpress specific genes which cause familial forms of the disease. Several of these tg mice display neuropathological and behavioral features of AD including amyloid beta-peptide (A beta) and amyloid deposits, neuritic plaques, gliosis, synaptic alterations and signs of neurodegeneration as well as memory impairment.

Immunotherapy for Alzheimer's disease: will vaccination work?

Active or passive immunization against the beta-amyloid peptide (Abeta) has been proposed as a method for preventing and/or treating Alzheimer's disease (AD). In addition to lowering brain Abeta and amyloid burden in transgenic mouse models of AD, a beneficial effect of immunization on previously characterized memory impairment(s) has also been reported in these mice. Whether these preclinical data will predict efficacy in AD patients remains to be seen.