AbstractAlzheimer’s Disease Progression Research Articles

IFN-γ Production by Amyloid β–Specific Th1 Cells Promotes Microglial Activation and Increases Plaque Burden in a Mouse Model of Alzheimer’s Disease

Alzheimer's disease (AD) is characterized by the presence of amyloid-β (Aβ)-containing plaques, neurofibrillary tangles, and neuronal loss in the brain. Inflammatory changes, typified by activated microglia, particularly adjacent to Aβ plaques, are also a characteristic of the disease, but it is unclear whether these contribute to the pathogenesis of AD or are a consequence of the progressive neurodegenerative processes. Furthermore, the factors that drive the inflammation and neurodegeneration remain poorly understood. CNS-infiltrating T cells play a pivotal role in the pathogenesis of multiple sclerosis, but their role in the progression of AD is still unclear. In this study, we examined the role of Aβ-specific T cells on Aβ accumulation in transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1). We found significant infiltration of T cells in the brains of APP/PS1 mice, and a proportion of these cells secreted IFN-γ or IL-17. Aβ-specific CD4 T cells generated by immunization with Aβ and a TLR agonist and polarized in vitro to Th1-, Th2-, or IL-17-producing CD4(+) T cells, were adoptively transferred to APP/PS1 mice at 6 to 7 mo of age. Assessment of animals 5 wk later revealed that Th1 cells, but not Th2 or IL-17-producing CD4(+) T cells, increased microglial activation and Aβ deposition, and that these changes were associated with impaired cognitive function. The effects of Th1 cells were attenuated by treatment of the APP/PS1 mice with an anti-IFN-γ Ab. Our study suggests that release of IFN-γ from infiltrating Th1 cells significantly accelerates markers of diseases in an animal model of AD.

Effects of Amyloid Beta Peptide on Neurovascular Cells.

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder, which is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in specific regions of the brain, accompanied by impairment of the neurons, and progressive deterioration of cognition and memory of affected individuals. Although the cause and progression of AD are still not well understood, the amyloid hypothesis is dominant and widely accepted. According to this hypothesis, an increased deposition of amyloid-β peptide (Aβ) in the brain is the main cause of the AD’s onset and progression. There is increasing body of evidence that blood-brain barrier (BBB) dysfunction plays an important role in the development of AD, and may even precede neuron degeneration in AD brain. In the early stage of AD, microvasculature deficiencies, inflammatory reactions, surrounding the cerebral vasculature and endothelial dysfunctions are commonly observed. Continuous neurovascular degeneration and accumulation of Aβ on blood vessels resulting in cerebral amyloid angiopathy is associated with further progression of the disease and cognitive decline. However, little is known about molecular mechanisms that underlie Aβ induced damage of neurovascular cells. In this regards, this review is aimed to address how Aβ impacts the cerebral endothelium. Understanding the cellular pathways triggered by Aβ leading to alterations in cerebral endothelial cells structure and functions would provide insights into the mechanism of BBB dysfunction and inflammatory processes in Alzheimer’s, and may offer new approaches for prevention and treatment strategies for AD.

Possible APOE Genotype and Sex Dependent Effects of 17-α- estradiol on Alzheimers Disease Pathology

Alzheimer’s disease (AD) remains the most prevalent cause of elderly dementia, posing an increasingly important health problem as the population ages [1]. AD is a neurodegenerative disorder defined by the presence of extracellular deposits of β-amyloid (Aβ), intraneuronal accumulations of neurofibrillary tangles containing hyperphosporylated tau protein, and the progressive loss of synapses and neurons that correlate with atrophy of brain regions [2]. Specific areas of the brain that show particularly severe neuronal loss include the entorhinal cortex, pyramidal neurons in the CA1 subregion of the hippocampus, and the noradrenergic neurons of the locus coeruleus [3-5]. The neuronal populations within these areas mediate attention, learning, memory and other neural processes associated with higher cognitive function. The specific mechanism(s) that underlie neuronal loss are not clearly understood, and there are no approved methods to slow this neurodegeneration. Of the risk factors identified that facilitate AD progression, the strongest are aging, the inheritance of the e4 allele of the Apolipoprotein E (APOE) gene, and sex - women have a higher incidence of AD than men [6]. The APOE gene encodes a 34 kDa protein that is the major protein component of CNS lipoproteins, involved in lipid transport and redistribution [7]. Even though there is no clear understanding of the role of APOE in AD pathology, the role of APOE4 isoform has been shown to affect synaptic structure, Aβ clearance and transport across blood brain barrier as well as energy metabolism [8]. In mice, APOE4 decrease dendritic spine density and neuronal complexity in various cortical brain regions [9]. In addition, APOE4 mice show impaired learning and memory in the Barnes maze tests [10]. These effects were observed in absence of significant Aβ accumulation suggesting Aβ independent mechanisms contributing to functional impairments in APOE4 carriers. There is a stronger association of APOE with AD in women than men that correlates well with greater hippocampal atrophy, plaque pathology and cognitive decline [11]. The gradual loss of sex steroid hormones in women may contribute to age associated cognitive decline [12]. A neuroprotective role of natural and synthetic estrogens in the mammalian brain has been established during the past decade. In particular, 17-β-estradiol (β-E2), has commonly been known to play a pivotal role in female reproductive physiology, enhances synaptic plasticity, neurite growth, hippocampal neurogliosis and long-term potentiation [13,14]. β-E2 is also effective in several neural injury and toxicity models. In animal models of AD, β-E2 reduces Aβ pathology and improves cognition [15], although the effectiveness of β-E2 is reduced in the presence of APOE4 [16]. This latter observation is consistent with a role for APOE in modulating the biological effects of estrogen-based therapy. Early estrogen replacement therapy prior to menopause has been shown to reduce the AD risk in postmenopausal women [17]. However the effects of β-E2 on peripheral targets in both men and women limit its usefulness as a potential therapy for AD. In the past decade concerns have been raised over the safety of long-term 17-β-E2 treatment as

Dynamic neuronal regulatory network during the progression of Alzheimer’s disease suggests an adaptive survival strategy

Alzheimer’s disease (AD) is the most common neurodegenerative disease. In this work, comprehensive analyses on transcriptome studies of human postmortem brain tissues from AD patients revealed stepwise breakdown of the cellular machinery during the progression of AD at semi-quantitative level. At the early stage of AD, the accumulation of A-beta oligomers and amyloid plaques leads to the down-regulation of biosynthesis and energy metabolism, likely a response to the reduced level of nutrient and oxygen supply. At the intermediate stage, the progression of the disease leads to enhanced signal transduction, also likely an adjustment to the deteriorating environment. The late stage is characterized by the elevated apoptosis due to the excessive regulatory and repair burden. Interestingly, the elevated apoptosis at the late stage is accompanied by elevated anti-apoptotic signals, suggesting an adaptive survival strategy even at the late stage of AD. These findings can serve as theoretical basis for pharmaceutical intervention of Alzheimer’s disease.

GPCR, a rider of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia that affects thinking, learning, memory and behavior of older people. Based on the previous studies, three pathogenic pathways are now commonly accepted as the culprits of this disease namely, amyloid-β pathway, tauopathology and cholinergic dysfunction. This review focuses on the current findings on the regulatory roles of G protein-coupled receptors (GPCRs) in the pathological progression of AD and discusses the potential of the GPCRs as novel therapeutic targets for AD.

Memantine in Moderate-to-severe Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia. It is a progressive neurodegenerative disorder resulting in cognitive and behavioural impairment of sufficient severity to markedly interfere with social and occupational functioning. The prevalence of AD increases steadily after the age of 65, with an estimated prevalence of approximately 50% in patients aged 85 or older. 1-2 Moreover, as the population ages, the proportion of the population affected by AD is predicted to increase dramatically. 3 AD is not only a heavy burden for the patient but is also responsible for making the patient dependent on his family or the community. Current pharmacotherapy is focused on delaying the symptomatic progression of AD. Although the cause of the disease remains unknown, acetylcholine deficiency, within a complex milieu of neurotransmitter changes in the brain, has been shown to play a role in AD. 4-5 By inhibiting the