Staged decline of neuronal function in vivo in an animal model of Alzheimer's disease

The accumulation of amyloid-β in the brain is an essential feature of Alzheimer's disease. However, the impact of amyloid-β-accumulation on neuronal dysfunction on the single cell level in vivo is poorly understood. Here we investigate the progression of amyloid-β load in relation to neuronal dysfunction in the visual system of the APP23×PS45 mouse model of Alzheimer's disease. Using in vivo two-photon calcium imaging in the visual cortex, we demonstrate that a progressive deterioration of neuronal tuning for the orientation of visual stimuli occurs in parallel with the age-dependent increase of the amyloid-β load. Importantly, we find this deterioration only in neurons that are hyperactive during spontaneous activity. This impairment of visual cortical circuit function also correlates with pronounced deficits in visual-pattern discrimination. Together, our results identify distinct stages of decline in sensory cortical performance in vivo as a function of the increased amyloid-β-load

Excitability and Synaptic Alterations in the Cerebellum of APP/PS1 Mice

In Alzheimer's disease (AD), the severity of cognitive symptoms is better correlated with the levels of soluble amyloid-beta (Aβ) rather than with the deposition of fibrillar Aβ in amyloid plaques. In APP/PS1 mice, a murine model of AD, at 8 months of age the cerebellum is devoid of fibrillar Aβ, but dosage of soluble Aβ1–42, the form which is more prone to aggregation, showed higher levels in this structure than in the forebrain. Aim of this study was to investigate the alterations of intrinsic membrane properties and of synaptic inputs in Purkinje cells (PCs) of the cerebellum, where only soluble Aβ is present. PCs were recorded by whole-cell patch-clamp in cerebellar slices from wild-type and APP/PS1 mice. In APP/PS1 PCs, evoked action potential discharge showed enhanced frequency adaptation and larger afterhyperpolarizations, indicating a reduction of the intrinsic membrane excitability. In the miniature GABAergic postsynaptic currents, the largest events were absent in APP/PS1 mice and the interspike intervals distribution was shifted to the left, but the mean amplitude and frequency were normal. The ryanodine-sensitive multivescicular release was not altered and the postsynaptic responsiveness to a GABAA agonist was intact. Climbing fiber postsynaptic currents were normal but their short-term plasticity was reduced in a time window of 100–800 ms. Parallel fiber postsynaptic currents and their short-term plasticity were normal. These results indicate that, in the cerebellar cortex, chronically elevated levels of soluble Aβ1–42 are associated with alterations of the intrinsic excitability of PCs and with alterations of the release of GABA from interneurons and of glutamate from climbing fibers, while the release of glutamate from parallel fibers and all postsynaptic mechanisms are preserved. Thus, soluble Aβ1–42 causes, in PCs, multiple functional alterations, including an impairment of intrinsic membrane properties and synapse-specific deficits, with differential consequences even in different subtypes of glutamatergic synapses

GABAA Receptor-Mediated Acceleration of Aging-Associated Memory Decline in APP/PS1 Mice and Its Pharmacological Treatment by Picrotoxin

Advanced age and mutations in the genes encoding amyloid precursor protein (APP) and presenilin (PS1) are two serious risk factors for Alzheimer's disease (AD). Finding common pathogenic changes originating from these risks may lead to a new therapeutic strategy. We observed a decline in memory performance and reduction in hippocampal long-term potentiation (LTP) in both mature adult (9–15 months) transgenic APP/PS1 mice and old (19–25 months) non-transgenic (nonTg) mice. By contrast, in the presence of bicuculline, a GABAA receptor antagonist, LTP in adult APP/PS1 mice and old nonTg mice was larger than that in adult nonTg mice. The increased LTP levels in bicuculline-treated slices suggested that GABAA receptor-mediated inhibition in adult APP/PS1 and old nonTg mice was upregulated. Assuming that enhanced inhibition of LTP mediates memory decline in APP/PS1 mice, we rescued memory deficits in adult APP/PS1 mice by treating them with another GABAA receptor antagonist, picrotoxin (PTX), at a non-epileptic dose for 10 days. Among the saline vehicle-treated groups, substantially higher levels of synaptic proteins such as GABAA receptor α1 subunit, PSD95, and NR2B were observed in APP/PS1 mice than in nonTg control mice. This difference was insignificant among PTX-treated groups, suggesting that memory decline in APP/PS1 mice may result from changes in synaptic protein levels through homeostatic mechanisms. Several independent studies reported previously in aged rodents both an increased level of GABAA receptor α1 subunit and improvement of cognitive functions by long term GABAA receptor antagonist treatment. Therefore, reduced LTP linked to enhanced GABAA receptor-mediated inhibition may be triggered by aging and may be accelerated by familial AD-linked gene products like Aβ and mutant PS1, leading to cognitive decline that is pharmacologically treatable at least at this stage of disease progression in mice

Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience

<p>Abstract</p> <p>Background</p> <p>Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of <it>APOE ε4 </it>allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to <it>APOE </it>genotype. With an eye toward defining ways in which <it>APOE ε3 </it>alleles may foster neuronal well-being in epilepsy and/or <it>APOE ε4 </it>alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either <it>APOE ε4,4 </it>or <it>APOE ε3,3 </it>genotype.</p> <p>Methods</p> <p>Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 <it>APOE ε3,3 </it>and 7 <it>APOE ε4,4 </it>(0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry.</p> <p>Results</p> <p>Tissue levels of IL-1α were elevated in patients of both <it>APOE ε3,3 </it>and <it>APOE ε4,4 </it>genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (<it>APOE </it>ε<it>3,3 </it>vs <it>APOE ε4,4 </it>= 3.7 ± 1.2 vs 1.5 ± 0.4; <it>P </it>< 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that <it>APOE ε4,4 </it>genotype was associated with smaller neuron size (<it>APOE ε4,4 </it>vs <it>APOE ε3,3 </it>= 173 ± 27 vs 356 ± 45; <it>P </it>≤ 0.01) and greater DNA damage (<it>APOE ε4,4 </it>vs <it>APOE ε3,3 </it>= 67 ± 10 vs 39 ± 2; <it>P </it>= 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of <it>APOE </it>genotype (<it>APOE ε4,4 </it>age 10; <it>APOE ε3,3 </it>age 17).</p> <p>Conclusions</p> <p>Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of <it>APOE ε3,3 </it>genotype compared to <it>APOE ε4,4 </it>genotype carriers, are consistent with the idea that the <it>APOE </it>ε<it>3,3 </it>genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).</p> <p>Please see related article: <url>http://www.biomedcentral.com/1741-7015/10/36</url></p

Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease

Experience-induced expression of immediate-early gene Arc/Arg3.1 is known to play a pivotal role in the consolidation of memory. Here we use in-vivo longitudinal multiphoton imaging to show orchestrated activity-dependent expression of Arc in the mouse extrastriate visual cortex in response to a structured visual stimulation. In wild-type mice, the amplitude of the Arc response in individual neurons strongly predicts the probability of reactivation by a subsequent presentation of the same stimulus. In a mouse model of Alzheimer’s disease, this association is markedly disrupted in the cortex specifically near senile plaques. Neurons in the vicinity of plaques are less likely to respond but, paradoxically, there is stronger response in those few neurons around plaques that do respond. To the extent that the orchestrated pattern of Arc expression reflects nervous system responses to, and physiological consolidation of, behavioral experience, the disruption in Arc patterns reveals plaque-associated interference with neural network integration

APP Intracellular Domain Impairs Adult Neurogenesis in Transgenic Mice by Inducing Neuroinflammation

A devastating aspect of Alzheimer's disease (AD) is the progressive deterioration of memory due to neuronal loss. Amyloid precursor protein (APP) occupies a central position in AD and APP-derived amyloid-β (Aβ) peptides are thought to play a pivotal role in disease pathogenesis. Nonetheless, it is becoming clear that AD etiology is highly complex and that factors other than Aβ also contribute to AD pathogenesis. APP intracellular domain (AICD) is generated together with Aβ and we recently showed that AICD transgenic mice recapitulate pathological features of AD such as tau hyperphosphorylation, memory deficits and neurodegeneration without increasing the Aβ levels. Since impaired adult neurogenesis is shown to augment memory deficits in AD mouse models, here we examined the status of adult neurogenesis in AICD transgenic mice.We previously generated transgenic mice co-expressing 59-residue long AICD fragment and its binding partner Fe65. Hippocampal progenitor cell proliferation was determined by BrdU incorporation at 1.5, 3 and 12 months of age. Only male transgenic and their respective wilt type littermate control mice were used. We find age-dependent decrease in BrdU incorporation and doublecortin-positive cells in the dentate gyrus of AICD transgenic mice suggesting impaired adult neurogenesis. This deficit resulted from decreased proliferation and survival, whereas neuronal differentiation remained unaffected. Importantly, this impairment was independent of Aβ since APP-KO mice expressing AICD also exhibit reduced neurogenesis. The defects in adult neurogenesis are prevented by long-term treatment with the non-steroidal anti-inflammatory agents ibuprofen or naproxen suggesting that neuroinflammation is critically involved in impaired adult neurogenesis in AICD transgenic mice.Since adult neurogenesis is crucial for spatial memory, which is particularly vulnerable in AD, these findings suggest that AICD can exacerbate memory defects in AD by impairing adult neurogenesis. Our findings further establish that AICD, in addition to Aβ, contributes to AD pathology and that neuroinflammation plays a much broader role in AD pathogenesis than previously thought

Early Induction of Oxidative Stress in Mouse Model of Alzheimer Disease with Reduced Mitochondrial Superoxide Dismutase Activity

While oxidative stress has been linked to Alzheimer's disease, the underlying pathophysiological relationship is unclear. To examine this relationship, we induced oxidative stress through the genetic ablation of one copy of mitochondrial antioxidant superoxide dismutase 2 (Sod2) allele in mutant human amyloid precursor protein (hAPP) transgenic mice. The brains of young (5–7 months of age) and old (25–30 months of age) mice with the four genotypes, wild-type (Sod2+/+), hemizygous Sod2 (Sod2+/−), hAPP/wild-type (Sod2+/+), and hAPP/hemizygous (Sod2+/−) were examined to assess levels of oxidative stress markers 4-hydroxy-2-nonenal and heme oxygenase-1. Sod2 reduction in young hAPP mice resulted in significantly increased oxidative stress in the pyramidal neurons of the hippocampus. Interestingly, while differences resulting from hAPP expression or Sod2 reduction were not apparent in the neurons in old mice, oxidative stress was increased in astrocytes in old, but not young hAPP mice with either Sod2+/+ or Sod2+/−. Our study shows the specific changes in oxidative stress and the causal relationship with the pathological progression of these mice. These results suggest that the early neuronal susceptibility to oxidative stress in the hAPP/Sod2+/− mice may contribute to the pathological and behavioral changes seen in this animal model

Clinical Audits in Outpatient Clinics for Chronic Obstructive Pulmonary Disease: Methodological Considerations and Workflow

Objectives: Previous clinical audits for chronic obstructive pulmonary disease (COPD) have provided valuable information on the clinical care delivered to patients admitted to medical wards because of COPD exacerbations. However, clinical audits of COPD in an outpatient setting are scarce and no methodological guidelines are currently available. Based on our previous experience, herein we describe a clinical audit for COPD patients in specialized outpatient clinics with the overall goal of establishing a potential methodological workflow.Methods: A pilot clinical audit of COPD patients referred to respiratory outpatient clinics in the region of Andalusia, Spain (over 8 million inhabitants), was performed. The audit took place between October 2013 and September 2014, and 10 centers (20% of all public hospitals) were invited to participate. Cases with an established diagnosis of COPD based on risk factors, clinical symptoms, and a post-bronchodilator FEV1/FVC ratio of less than 0.70 were deemed eligible. The usefulness of formally scheduled regular follow-up visits was assessed. Two different databases (resources and clinical database) were constructed. Assessments were planned over a year divided by 4 three-month periods, with the goal of determining seasonal-related changes. Exacerbations and survival served as the main endpoints.Conclusions: This paper describes a methodological framework for conducting a clinical audit of COPD patients in an outpatient setting. Results from such audits can guide health information systems development and implementation in real-world settings.This study was financially supported by an unrestricted grant from Laboratorios Menarini, SA (Barcelona, Spain)

An Epigenetic Blockade of Cognitive Functions in the Neurodegenerating Brain

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade