Endoplasmic reticulum-Mitochondria Coupling in Alzheimer's Disease.

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Mitochondrial bioenergetics and neurodegeneration: a paso doble

Memory loss in Alzheimer's disease: are the alterations in the UPR network involved in the cognitive impairment?

Nilotinib: from animal-based studies to clinical investigation in Alzheimer's disease patients.

The study aimed to examine the behavior ability and morphological changes in neuron in the hippocampal CA3 area of Alzheimer's disease (AD) model rats induced by β-amyloid protein (Aβ1–42) and observe the potentiality of the neuroprotective effect of basic fibroblast growth factor (bFGF) on the AD model rats. A total of 70 Wistar rats were randomly divided into the normal control group, the AD model group and the bFGF treatment group. The AD model rats were established by microinjection of Aβ1–42 solution into right hippocampal CA1 area. The bFGF was injected into the abdominal cavity of rats in the bFGF treatment group, and identical volume physiological saline was given for the other two groups. The colorimetric method was used to detect the choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) activity after the behavior capability was determined. Real time-PCR (RT-PCR) was used to evaluate the expression of VEGF mRNA of the rat hippocampal CA3 area. Caspase-3 immunopositive cells in the hippocampal CA3 area were observed under a light microscopy and quantitative analysis were performed by cell morphometric technique. The ultra-microstructure of the neurons was also observed by a transmission electron microscopy (TEM). The results indicated that compared with the AD model group, the learning and memory abilities of the bFGF treatment group were obviously improved and the ChAT activity significantly increased (p < 0.05), whereas the AChE activity, expression of VEGF mRNA and quantity of Caspase-3 immunopositive cells notably decreased (p < 0.05). Under TEM, the neurons in the hippocampal CA3 area of the normal control group had moderate electron density, rule nucleus, integrity perinuclear membrane, evenly distributed chromoplasm and abundant cell organelle, however the neurons of the AD model group showed severely damaged, exhibiting cell body pyknosis, irregular nuclear membranes concentrated, intracytoplasm content concentrated, decreased or unclear organelles. The neuronic pathological lesion of the bFGF treatment group had lessened than that of the AD model group; some of them had distinct neuronal structure and abundant cell organelle. BFGF could efficiently improve the behavior ability and decrease the pathological lesion of hippocampus of the AD model rats, which might promote the neuroprotective effect in the AD.

While the greatest risk factor for Alzheimer's disease (AD) is aging, women are disproportionately affected by the disease. Interestingly, the hippocampus and cerebellum exhibit gender-specific cytoarchitecture differences, which are associated with AD, despite the absence of a role in animal reproductive behavior or hormonal signaling. This study investigates the potential association of sex differences associated with AD by interrogating cerebellar and hippocampal volume in preclinical (MCI) as well as clinical phases of AD compared to cognitively normal patients (CN) and in an animal model of AD, the streptozotocin (STZ)-induced sporadic AD model. In order to investigate putative changes in cerebellum and hippocampus in a rat model of AD, we used a STZ-induced sporadic AD model at three different time points (2, 4, and 8 weeks) after surgery in male and female rats. Previous studies have reported hippocampal-dependent changes as well as sex-dependent behavioral and signaling effects in the STZ animal model of sporadic AD while our current study showed involvement of cerebellum-mediated changes. To interrogate the role of cerebellar volume in AD progression within the human context, we analyzed data available through the Alzheimer's Disease Neuroimaging Initiative (ADNI). In a cross-sectional analysis, we observed that levels of peripheral Glial Acidic Fibrillary Protein (GFAP) (astrocytic protein) were associated negatively with cerebellar and hippocampal volumes (β = -0.002, p-value = 0.04; β = -6.721, p-value < 0.0001) and were associated with sex specific differences in males. Our analysis identified that the effect on hippocampal volume was earlier in disease stage, reinforcing the relevance of longitudinal alterations of cerebellum and hippocampus volume over time. The STZ animal model of sporadic AD, corroborated the progressive changes in hippocampal volume and more minor and temporally delayed involvement of the cerebellum volume changes which were dependent on sex. This suggests that cerebellar involvement may be secondary to hippocampal neurodegeneration, and both regional differences were dependent on sex. Due to the association with GFAP, our findings may be due to network astrocyte connection spread regardless of primary pathology. Overall, our study uncovers a novel role for cerebellum in AD in a model and in the human context.

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Protein aggregation is invariably associated with the inflammation as a factor in Alzheimer's disease (AD). We investigated the interaction between downstream factors of endoplasmic reticulum (ER) stress pathway and inflammation, with implications in cognitive impairment in AD. Amyloid-β(Aβ)(1-42) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats to experimentally develop AD. The cognitive impairment was assessed by measuring behavioral parameters such as Morris water maze and novel object recognition tests. Levels of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-inflammatory cytokines IL-4 and IL-10 were measured by the enzyme-linked immunosorbent assay (ELISA) in different rat brain regions. Inflammatory marker proteins such as cyclo-oxygenase (COX)-2 and phosphorylation of nuclear factor kappa B(NF-КB) (p65) were measured by the western blotting. Gene expression of ER stress downstream factors such as ATF-4, CHOP, and GADD-34 was analyzed by qRT-PCR. Histological studies were performed to check Aβ accumulation and neuronal degeneration. Integrated stress response inhibitor (ISRIB) was used to confirm the specific role of ER stress-mediated inflammation in cognitive impairment. Administration of Aβ(1-42) resulted in alteration in levels of inflammatory cytokines, inflammatory proteins, and mRNA levels of ER stress downstream factors. ISRIB treatment resulted in attenuation of Aβ(1-42)-induced ER stress, inflammation, neurodegeneration, and cognitive impairment in rats. These results indicate that ER stress-mediated inflammation potentiates the cognitive impairment in AD. An understanding of cascade of events, interaction of ER stress which was a hallmark of the present investigation together with inflammation and modulation of downstream signalling factors could serve as potent biomarkers to study AD progression.

Animal Models of Alzheimer's Disease

Shifting balance from neurodegeneration to regeneration of the brain: a novel therapeutic approach to Alzheimer's disease and related neurodegenerative conditions.

Objective To investigate the effect of Fructus arctii extract on Alzheimer disease (AD) model of mice and its mechanism. Methods Fifty healthy male Kunming mice were randomly divided into 5 groups, respectively, the negative control group, AD model group, Oxiracetam Capsules (400 mg/kg) and Fructus arctii extract (FAE 800 mg/kg, 400 mg/kg). The AD model was intraperitoneally injected with D-galactose 100 mg/kg and aluminum trichloride 10 mg/kg by intragastric administration every day. Since the 15th day of AD model developed, the mice in experimental groups were intragastric administrated with the corresponding dosage each day for 45 days. Behavioral testing in exposed and control mice were developed using step-down assays and water maze test, and the chemical parameters SOD, T-AOC, MDA, [Ca2+], NO and NOS of brain tissue were measured. Differences among groups were compared by SPSS statistics software using ANOVA. Results Compared with model group, the latency period in step-down assays was statistically lengthened and the whole swimming time in water maze test was reduced in the FAE groups, and the rate of errors was decreased in step-down tests (F=11.07, P=0.004. F=8.13, P=0.011, F=6.25, P=0.02). The chemical parameter showed that the levels of MDA, NO, NOS and [Ca2+] in brain tissue were significantly decreased in the FAE group (F=5.12, P=0.04 F=4.49, P=0.05, F=4.55, P=0.05, F=4.62, P=0.05) and the activity of the SOD and T-AOC (F=6.49, P=0.02. F=4.76, P=0.05) increased greatly. Conclusions The FAE can protect the deficit of learning and memory of the AD model mice. The mechanisms of effects may be related to the improvement of enzymes, reduce the formation of free radical; resulting in prevention of peroxide generation and reduction of NO-related neurological damage. Key words: Fructus arctii; Alzheimer disease; Learning and memory; Model

The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD). Because abnormalities in Ca2+ signaling have been observed in several AD models, we investigated TREM2 regulation of Ca2+ signaling in human induced pluripotent stem cell-derived microglia (iPSC-microglia) with genetic deletion of TREM2. We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca2+ signals in response to purinergic agonists, such as ADP, that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y12 and P2Y13 receptors, results in greater release of Ca2+ from the endoplasmic reticulum stores, which triggers sustained Ca2+ influx through Orai channels and alters cell motility in TREM2 KO microglia. Using iPSC-microglia expressing the genetically encoded Ca2+ probe, Salsa6f, we found that cytosolic Ca2+ tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic Ca2+ using a P2Y12 receptor antagonist. Our results show that loss of TREM2 confers a defect in microglial Ca2+ response to purinergic signals, suggesting a window of Ca2+ signaling for optimal microglial motility.

Dysregulated endoplasmic reticulum (ER) calcium (Ca2+) signaling is reported to play an important role in Alzheimer disease (AD) pathogenesis. The role of ER Ca2+ release channels, the ryanodine receptors (RyanRs), has been extensively studied in AD models and RyanR expression and activity are upregulated in the brains of various familial AD (FAD) models. The objective of this study was to utilize a genetic approach to evaluate the importance of RyanR type 3 (RyanR3) in the context of AD pathology.

Extracts from two ubiquitous Mediterranean plants ameliorate cellular and animal models of neurodegenerative proteinopathies

Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E2 (PGE2) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE2 EP2 receptor in the APPSwe-PS1DeltaE9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-beta (Abeta) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1DeltaE9 mice lacking the EP2 receptor harbor lower levels of beta C-terminal fragments, the product of beta-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased Abeta peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.