Acute stressors do not impair short-term memory or attention in an aged mouse model of amyloidosis.

Memory impairment in Alzheimer's disease patients is thought to be associated with the accumulation of amyloid-beta peptides and tau proteins. However, inconsistent reports of cognitive deficits in pre-clinical studies have raised questions about the link between amyloid-beta and cognitive decline. One possible explanation may be that studies reporting memory deficits often involve behavioral assessments that entail a high stress component.

Longitudinal assessment of cognitive function in the APPswe/PS1dE9 mouse model of Alzheimer's-related beta-amyloidosis.

Preclinical models of Alzheimer's disease (AD)-related cognitive decline can be useful for developing therapeutics. The current study longitudinally assessed short-term memory, using a delayed matching-to-position (DMTP) task, and attention, using a 3-choice serial reaction time (3CSRT) task, from approximately 18 weeks of age through death or 72 weeks of age in APPswe/PS1dE9 mice, a widely used mouse model of AD-related amyloidosis. Both transgenic (Tg) and non-Tg mice exhibited improvements in DMTP accuracy over time.

NMDA Receptor-Arc Signaling Is Required for Memory Updating and Is Disrupted in Alzheimer's Disease.

Background: Memory deficits are central to many neuropsychiatric diseases. During acquisition of new information, memories can become vulnerable to interference, yet mechanisms that underlie interference are unknown.

Methods: We describe a novel transduction pathway that links the NMDA receptor (NMDAR) to AKT signaling via the immediate early gene Arc and evaluate its role in memory.

Hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-like behavior during aging: A test of the glucocorticoid cascade hypothesis in amyloidogenic APPswe/PS1dE9 mice.

Alzheimer's disease (AD) is a progressive, dementing, whole-body disorder that presents with decline in cognitive, behavioral, and emotional functions, as well as endocrine dysregulation. The etiology of AD is not fully understood but stress- and anxiety-related hormones may play a role in its development and trajectory. The glucocorticoid cascade hypothesis posits that levels of glucocorticoids increase with age, leading to dysregulated negative feedback, further elevated glucocorticoids, and resulting neuropathology.

Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of α-synucleinopathy.

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer's disease.

PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R).

While neuroinflammation is an evolving concept and the cells involved and their functions are being defined, microglia are understood to be a key cellular mediator of brain injury and repair. The ability to measure microglial activity specifically and noninvasively would be a boon to the study of neuroinflammation, which is involved in a wide variety of neuropsychiatric disorders including traumatic brain injury, demyelinating disease, Alzheimer's disease (AD), and Parkinson's disease, among others. We have developed [C]CPPC [5-cyano--(4-(4-[C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide], a positron-emitting, high-affinity ligand that is specific for the macrophage colony-stimulating factor 1 receptor (CSF1R), the expression of which is essentially restricted to microglia within brain.

Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation.

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome.

Association between serotonin denervation and resting-state functional connectivity in mild cognitive impairment.

Resting-state functional connectivity alterations have been demonstrated in Alzheimer's disease (AD) and mild cognitive impairment (MCI) before the observation of AD neuropathology, but mechanisms driving these changes are not well understood. Serotonin neurodegeneration has been observed in MCI and AD and is associated with cognitive deficits and neuropsychiatric symptoms, but the role of the serotonin system in relation to brain network dysfunction has not been a major focus of investigation. The current study investigated the relationship between serotonin transporter availability (SERT; measured using positron emission tomography) and brain network functional connectivity (measured using resting-state functional MRI) in 20 participants with MCI and 21 healthy controls.

Increased Sparsity of Hippocampal CA1 Neuronal Ensembles in a Mouse Model of Down Syndrome Assayed by Arc Expression.

Down syndrome (DS) is the leading chromosomal cause of intellectual disability, yet the neural substrates of learning and memory deficits remain poorly understood. Here, we interrogate neural networks linked to learning and memory in a well-characterized model of DS, the Ts65Dn mouse. We report that Ts65Dn mice exhibit exploratory behavior that is not different from littermate wild-type (WT) controls yet behavioral activation of Arc mRNA transcription in pyramidal neurons of the CA1 region of the hippocampus is altered in Ts65Dn mice.

Sex-related dimorphism in dentate gyrus atrophy and behavioral phenotypes in an inducible tTa:APPsi transgenic model of Alzheimer's disease.

Sex differences are a well-known phenomenon in Alzheimer's disease (AD), with women having a higher risk for AD than men. Many AD mouse models display a similar sex-dependent pattern, with females showing earlier cognitive deficits and more severe neuropathology than males. However, whether those differences are relevant to human disease is unclear.

Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation.

In Alzheimer's disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors.

Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice.

Background: Though the precise cause(s) of Alzheimer's disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs).

Alzheimer's therapeutics: translation of preclinical science to clinical drug development.

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation-from how we model the disease to how we run clinical trials.

Synthesis and biodistribution of [11C]A-836339, a new potential radioligand for PET imaging of cannabinoid type 2 receptors (CB2).

Recently, A-836339 [2,2,3,3-tetramethylcyclopropanecarboxylic acid [3-(2-methoxyethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]amide] (1) was reported to be a selective CB2 agonist with high binding affinity. Here we describe the radiosynthesis of [11C]A-836339 ([11C]1) via its desmethyl precursor as a candidate radioligand for imaging CB2 receptors with positron-emission tomography (PET). Whole body and the regional brain distribution of [11C]1 in control CD1 mice demonstrated that this radioligand exhibits specific uptake in the CB2-rich spleen and little specific in vivo binding in the control mouse brain.

Partial depletion of CREB-binding protein reduces life expectancy in a mouse model of Huntington disease.

Previous studies have reported that mutant huntingtin (htt) interferes with cyclic AMP response element binding protein binding protein (CBP)-mediated transcription, possibly by inhibiting the acetylation of histones. In Drosophila models that express fragments of mutant htt, histone deacetylase inhibitors reverse deficits in histone acetylation, rescue photoreceptor degeneration, and prolong their survival. These compounds also improve motor deficits in a transgenic mouse model of Huntington disease (HD).

Modeling an anti-amyloid combination therapy for Alzheimer's disease.

As only symptomatic treatments are now available for Alzheimer's disease (AD), safe and effective mechanism-based therapies remain a great unmet need for patients with this neurodegenerative disease. Although gamma-secretase and BACE1 [beta-site beta-amyloid (Abeta) precursor protein (APP) cleaving enzyme 1] are well-recognized therapeutic targets for AD, untoward side effects associated with strong inhibition or reductions in amounts of these aspartyl proteases have raised concerns regarding their therapeutic potential. Although moderate decreases of either gamma-secretase or BACE1 are not associated with mechanism-based toxicities, they provide only modest benefits in reducing Abeta in the brains of APPswe/PS1DeltaE9 mice.

Amyloid precursor protein increases cortical neuron size in transgenic mice.

The amyloid precursor protein (APP) is the source of beta-amyloid, a pivotal peptide in the pathogenesis of Alzheimer's disease (AD). This study examines the possible effect of APP transgene expression on neuronal size by measuring the volumes of cortical neurons (microm(3)) in transgenic mouse models with familial AD Swedish mutation (APPswe), with or without mutated presenilin1 (PS1dE9), as well as in mice carrying wild-type APP (APPwt). Overexpression of APPswe and APPwt protein, but not of PS1dE9 alone, resulted in a greater percentage of medium-sized neurons and a proportionate decrease in the percentage of small-sized neurons.

Morphometry of the human substantia nigra in ageing and Parkinson's disease.

To investigate the relation between the loss of substantia nigra (SN) neurons in normal ageing and Parkinson's disease (PD), we measured the total number and the cell body volume of pigmented (neuromelanin) neurons in the SN. We examined young (n = 7, mean age: 19.9), middle-aged (n = 9, mean age: 50.

BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions.

A transmembrane aspartyl protease termed beta-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-beta (Abeta) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to Abeta amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of Abeta in the CNS, whereas other organs are spared.

Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease.

Background: The proteases (secretases) that cleave amyloid-beta (Abeta) peptide from the amyloid precursor protein (APP) have been the focus of considerable investigation in the development of treatments for Alzheimer disease. The prediction has been that reducing Abeta production in the brain, even after the onset of clinical symptoms and the development of associated pathology, will facilitate the repair of damaged tissue and removal of amyloid lesions. However, no long-term studies using animal models of amyloid pathology have yet been performed to test this hypothesis.

Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease.

Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment.

Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice.

Huntington's disease (HD) results from the expansion of a glutamine repeat near the N-terminus of huntingtin (htt). At post-mortem, neurons in the central nervous system of patients have been found to accumulate N-terminal fragments of mutant htt in nuclear and cytoplasmic inclusions. This pathology has been reproduced in transgenic mice expressing the first 171 amino acids of htt with 82 glutamines along with losses of motoric function, hypoactivity and abbreviated life-span.

Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice.

The HD-N171-82Q (line 81) mouse model of Huntington's disease (HD), expresses an N-terminal fragment of mutant huntingtin (htt), loses motor function, displays HD-related pathological features, and dies prematurely. In the present study, we compare the efficacy with which environmental, pharmacological, and genetic interventions ameliorate these abnormalities. As previously reported for the R6/2 mouse model of HD, housing mice in enriched environments improved the motor skills of N171-82Q mice.

Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE.

Amyloid deposition appears to be an early and crucial event in Alzheimer's disease (AD). To generate animal models of AD, mice expressing full-length amyloid precursor protein (APP), with mutations linked to FAD, have been created. These animals exhibit abnormalities characteristic of AD, including deposits of beta-amyloid (Abeta), neuritic plaques, and glial responses.

Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats.

Recent studies suggest that some aspects of learning and memory may be altered by a midlife loss of estrogen, indicating a potential causal relationship between the deficiency of ovarian hormones and cognitive aging. In this study, the effects of estrogen withdrawal and replacement were tested in middle-aged Fischer-344 rats using different memory tasks. Estrogen withdrawal accelerated the rate of cognitive aging.