Accumulation Of Phosphorylated Tau Research Articles

Evidence of Synaptic and Neurochemical Remodeling in the Retina of Aging Degus.

Accumulation of amyloid-beta (Aβ) peptides is regarded as the hallmark of neurodegenerative alterations in the brain of Alzheimer’s disease (AD) patients. In the eye, accumulation of Aβ peptides has also been suggested to be a trigger of retinal neurodegenerative mechanisms. Some pathological aspects associated with Aβ levels in the brain are synaptic dysfunction, neurochemical remodeling and glial activation, but these changes have not been established in the retina of animals with Aβ accumulation. We have employed the Octodon degus in which Aβ peptides accumulated in the brain and retina as a function of age. This current study investigated microglial morphology, expression of PSD95, synaptophysin, Iba-1 and choline acetyltransferase (ChAT) in the retina of juvenile, young and adult degus using immunolabeling methods. Neurotransmitters glutamate and gamma-aminobutyric acid (GABA) were detected using immunogold labeling and glutamate receptor subunits were quantified using Western blotting. There was an age-related increase in presynaptic and a decrease in post-synaptic retinal proteins in the retinal plexiform layers. Immunolabeling showed changes in microglial morphology characteristic of intermediate stages of activation around the optic nerve head (ONH) and decreasing activation toward the peripheral retina. Neurotransmitter expression pattern changed at juvenile ages but was similar in adults. Collectively, the results suggest that microglial activation, synaptic remodeling and neurotransmitter changes may be consequent to, or parallel to Aβ peptide and phosphorylated tau accumulation in the retina.

Antiviral therapy: Valacyclovir Treatment of Alzheimer’s Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial

IntroductionAfter infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can enter the brain via retrograde axonal transport. Recurrent reactivation of HSV1 may lead to neurodegeneration and...

Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model

Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia are characterized by neuronal expression of aberrant tau protein, tau hyperphosphorylation (pTAU), tau aggregation and neurofibrillary tangle formation sequentially culminating into neuronal cell death, a process termed tauopathy. Our aim was to address at which tauopathy stage neuroinflammation starts and to study the related microglial phenotype. We used Thy1-hTau.P301S (PS) mice expressing human tau with a P301S mutation specifically in neurons. Significant levels of cortical pTAU were present from 2 months onwards. Dystrophic morphological complexity of cortical microglia arose after pTAU accumulation concomitant with increased microglial lysosomal volumes and a significant loss of homeostatic marker Tmem119. Interestingly, we detected increases in neuronal pTAU and postsynaptic structures in the lysosomes of PS microglia. Moreover, the overall cortical postsynaptic density was decreased in 6-month-old PS mice. Together, our results indicate that microglia adopt a pTAU-associated phenotype, and are morphologically and functionally distinct from wild-type microglia after neuronal pTAU accumulation has initiated.

Transcriptional profiling predicts running promotes cerebrovascular remodeling in young but not midlife mice

BackgroundThe incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer’s disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood.ResultsTo better understand the effects of exercise, we preformed transcriptional profiling on young (1–2 months) and midlife (12 months) C57BL/6 J (B6) male mice after 12 weeks of voluntary running. Data was compared to age-matched sedentary controls. Interestingly, the midlife running group naturally broke into two cohorts based on distance ran - either running a lot and more intensely (high runners) or running less and less intensely (low runners). Midlife high runners had lower LDL cholesterol as well as lower adiposity (%fat) compared to sedentary, than midlife low runners compared to sedentary suggesting more intense running lowered systemic markers of risk for age-related diseases including dementias. Differential gene analysis of transcriptional profiles generated from the cortex and hippocampus showed thousands of differentially expressed (DE) genes when comparing young runners to sedentary controls. However, only a few hundred genes were DE comparing either midlife high runners or midlife low runners to midlife sedentary controls. This indicates that, in our study, the effects of running are reduced through aging. Gene set enrichment analyses identified enrichment of genes involved in extracellular matrix (ECM), vascular remodeling and angiogenesis in young runners but not midlife runners. These genes are known to be expressed in multiple vascular-related cell types including astrocytes, endothelial cells, pericytes and smooth muscle cells.ConclusionsTaken together these results suggest running may best serve as a preventative measure to reduce risk for cerebrovascular decline. Ultimately, this work shows that exercise may be more effective to prevent dementia if introduced at younger ages.

Gut microbiota manipulation through probiotics oral administration restores glucose homeostasis in a mouse model of Alzheimer's disease

Cerebral glucose homeostasis deregulation has a role in the pathogenesis and the progression of Alzheimer's disease (AD). Current therapies delay symptoms without definitively curing AD. We have previously shown that probiotics counteract AD progression in 3xTg-AD mice modifying gut microbiota and inducing energy metabolism and glycolysis-gluconeogenesis. Ameliorated cognition is based on higher neuroprotective gut hormones concentrations, reduced amyloid-β burden, and restored proteolytic pathways. Here, we demonstrate that probiotics oral administration improves glucose uptake in 3xTg-AD mice by restoring the brain expression levels of key glucose transporters (GLUT3, GLUT1) and insulin-like growth factor receptor β, in accordance with the diminished phosphorylation of adenosine monophosphate–activated protein kinase and protein-kinase B (Akt). In parallel, phosphorylated tau aggregates decrease in treated mice. Probiotics counteract the time-dependent increase of glycated hemoglobin and the accumulation of advanced glycation end products in AD mice, consistently with memory improvement. Collectively, our data elucidate the mechanism through which gut microbiota manipulation ameliorates impaired glucose metabolism in AD, finally delaying the disease progression.

Association of White Matter Rarefaction, Arteriolosclerosis, and Tau With Dementia in Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts, including those from US football, that presents with cognitive and neuropsychiatric disturbances that can progress to dementia. Pathways to dementia in CTE are unclear and likely involve tau and nontau pathologic conditions. To investigate the association of white matter rarefaction and cerebrovascular disease with dementia in deceased men older than 40 years who played football and had CTE. This cross-sectional study involves analyses of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study, which is conducted via and included brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank between 2008 and 2017. An original sample of 224 men who had played football and were neuropathologically diagnosed with CTE was reduced after exclusion of those younger than 40 years and those missing data. The number of years of football play as a proxy for repetitive head impacts. Neuropathological assessment of white matter rarefaction and arteriolosclerosis severity (on a scale of 0-3, where 3 is severe); number of infarcts, microinfarcts, and microbleeds; and phosphorylated tau accumulation determined by CTE stage and semiquantitative rating of dorsolateral frontal cortex (DLFC) neurofibrillary tangles (NFTs) (none or mild vs moderate or severe). Informant-based retrospective clinical interviews determined dementia diagnoses via diagnostic consensus conferences. A total of 180 men were included. The mean (SD) age of the sample at death was 67.9 (12.7) years. Of 180, 120 [66.7%]) were found to have had dementia prior to death. Moderate to severe white matter rarefaction (84 of 180 [46.6%]) and arteriolosclerosis (85 of 180 [47.2%]) were common; infarcts, microinfarcts, and microbleeds were not. A simultaneous equations regression model controlling for age and race showed that more years of play was associated with more severe white matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and greater phosphorylated tau accumulation (DLFC NFTs: β, 0.15 [95% CI, 0.004-0.30]; P = .04; CTE stage: β, 0.27 [95% CI, 0.14-0.41]; P < .001). White matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and DLFC NFTs (β, 0.16 [95% CI, 0.03-0.28]; P = .01) were associated with dementia. Arteriolosclerosis and years of play were not associated, but arteriolosclerosis was independently associated with dementia (β, 0.21 [95% CI, 0.07-0.35]; P = .003). Among older men who had played football and had CTE, more years of football play were associated with more severe white matter rarefaction and greater DLFC NFT burden. White matter rarefaction, arteriolosclerosis, and DLFC NFTs were independently associated with dementia. Dementia in CTE is likely a result of neuropathologic changes, including white matter rarefaction and phosphorylated tau, associated with repetitive head impact and pathologic changes not associated with head trauma, such as arteriolosclerosis.

Lipopolysaccharide exposure in a rat sepsis model results in hippocampal amyloid-β plaque and phosphorylated tau deposition and corresponding behavioral deficits

Sepsis is a severe systemic inflammatory response to infection associated with acute and chronic neurocognitive consequences, including an increased risk of later-life dementia. In a lipopolysaccharide-induced rat sepsis model, we have demonstrated neuroinflammation, cortical amyloid-beta plaque deposition, and increased whole brain levels of phosphorylated tau. Hippocampal abnormalities, particularly those of the dentate gyrus, are seen in Alzheimer's disease and age-related memory loss. The focus of this study was to determine whether Aβ plaques and phosphorylated tau aggregates occur in the hippocampus as a consequence of lipopolysaccharide administration, and whether behavioral abnormalities related to the hippocampus, particularly the dentate gyrus, can be demonstrated. Male Sprague Dawley rats received an intraperitoneal injection of 10mg/kg of lipopolysaccharide endotoxin. Control animals received a saline injection. Seven days post injection, Aβ plaques and phosphorylated tau in the hippocampus were quantified following immunostaining. Behavioral tests that have previously been shown to result in specific deficits in dentate gyrus-lesioned rats were administered. Lipopolysaccharide treatment results in the deposition of beta amyloid plaques and intracellular phosphorylated tau in the hippocampus, including the dorsal dentate gyrus. Lipopolysaccharide treatment resulted in behavioral deficits attributable to the dorsal dentate gyrus, including episodic-like memory function that primarily involves spatial, contextual, and temporal orientation and integration. Lipopolysaccharide administration results in hippocampal deposition of amyloid-beta plaques and intracellular phosphorylated tau and results in specific behavioral deficits attributable to the dorsal dentate gyrus. These findings, if persistent, could provide a basis for the higher rate of dementia in longitudinal studies of sepsis survivors.

Influx of Tau and Amyloid-β Proteins into the Blood During Hemodialysis as a Therapeutic Extracorporeal Blood Amyloid-β Removal System for Alzheimer's Disease.

The accumulation of amyloid-β protein (Aβ) and tau in the brain is a major pathological change related to Alzheimer's disease. We have continued to develop Extracorporeal Blood Aβ Removal Systems (E-BARS) as a method for enhancing Aβ clearance from the brain. Our previous report revealed that dialyzers effectively remove blood Aβ and evoke large Aβ influxes into the blood, resulting in a decrease in brain Aβ accumulation after initiating hemodialysis, and that patients who underwent hemodialysis had lower brain Aβ accumulation than those who did not. Here, plasma total tau concentrations from 30 patients undergoing hemodialysis were measured using an ultrasensitive immunoassay and compared to those from 11 age-matched controls. Plasma total tau concentrations were higher in patients with renal failure regardless of whether they underwent hemodialysis, suggesting the involvement of the kidneys in tau degradation and excretion. Hemodialyzers effectively removed blood Aβ but not extracorporeal blood tau. The influx of tau into the blood was observed at around the 1 h period during hemodialysis sessions. However, the influx amount of tau was far smaller than that of Aβ. Furthermore, histopathological analysis revealed similar, not significantly less, cerebral cortex phosphorylated tau accumulation between the 17 patients who underwent hemodialysis and the 16 age-matched subjects who did not, although both groups showed sparse accumulation. These findings suggest that hemodialysis may induce both tau and Aβ migration into the blood. However, as a therapeutic strategy for Alzheimer's disease, it may only be effective for removing Aβ from the brain.

Microglial priming of antigen presentation and adaptive stimulation in Alzheimer's disease.

The prominent pathological consequences of Alzheimer's disease (AD) are the misfolding and mis-sorting of two cellular proteins, amyloid-β and microtubule-associated protein Tau. The accumulation of toxic phosphorylated Tau inside the neurons induces the increased processing of amyloid-β-associated signaling cascade and vice versa. Neuroinflammation-driven synaptic depletion and cognitive decline are substantiated by the cross talk of activated microglia and astroglia, leading to neuron degeneration. Microglia are the brain-resident immune effectors that prove their diverse functions in maintaining CNS homeostasis via collaboration with astrocytes and T lymphocytes. Age-related senescence and chronic inflammation activate microglia with increased pro-inflammatory markers, oxidative damage and phagocytosis. But the improper processing of misfolded protein via lysosomal pathway destines the spreading of 'seed' constituents to the nearby healthy neurons. Primed microglia process and present self-antigen such as amyloid-β and modified Tau to the infiltrated T lymphocytes through MHC I/II molecules. After an effective conversation with CD4+ T cells, microglial phenotype can be altered from pro-active M1 to neuro-protective M2 type, which corresponds to the tissue remodeling and homeostasis. In this review, we are focusing on the change in functionality of microglia from innate to adaptive immune response in the context of neuroprotection, which may help in the search of novel immune therapy in AD.

AD molecular: Molecular imaging of Alzheimer's disease: PET imaging of neurotransmitter systems.

Current understanding of Alzheimer's disease (AD) pathogenesis relies on the observed accumulations of amyloid β and phosphorylated tau aggregates that are thought to play key roles in initiating or propagating disease. However, other processes including changes in synaptic proteins and neurotransmitter loss have been suggested as important etiologies or contributors. Positron emission tomography (PET) imaging allows in vivo investigations of molecular changes associated with AD. PET imaging with multiple radiotracers can be used in combination with other modalities such as magnetic resonance imaging (MRI), and with assessments of cognition and neuropsychiatric symptoms to investigate the molecular underpinnings of AD. Studies of synaptic protein changes may improve the understanding of disease mechanisms and provide valuable markers of disease progression and therapeutic efficacy. This chapter will illustrate the importance of in vivo molecular imaging in the study of AD with a specific emphasis on PET and radioligands for several non-amyloid targets.

Characterisation of tau in the human and rodent enteric nervous system under physiological conditions and in tauopathy

Tau is normally a highly soluble phosphoprotein found predominantly in neurons. Six different isoforms of tau are expressed in the adult human CNS. Under pathological conditions, phosphorylated tau aggregates are a defining feature of neurodegenerative disorders called tauopathies. Recent findings have suggested a potential role of the gut-brain axis in CNS homeostasis, and therefore we set out to examine the isoform profile and phosphorylation state of tau in the enteric nervous system (ENS) under physiological conditions and in tauopathies. Surgical specimens of human colon from controls, Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) patients were analyzed by Western Blot and immunohistochemistry using a panel of anti-tau antibodies. We found that adult human ENS primarily expresses two tau isoforms, localized in the cell bodies and neuronal processes. We did not observe any difference in the enteric tau isoform profile and phosphorylation state between PSP, PD and control subjects. The htau mouse model of tauopathy also expressed two main isoforms of human tau in the ENS, and there were no apparent differences in ENS tau localization or phosphorylation between wild-type and htau mice. Tau in both human and mouse ENS was found to be phosphorylated but poorly susceptible to dephosphorylation with lambda phosphatase. To investigate ENS tau phosphorylation further, primary cultures from rat enteric neurons, which express four isoforms of tau, were pharmacologically manipulated to show that ENS tau phosphorylation state can be regulated, at least in vitro. Our study is the first to characterize tau in the rodent and human ENS. As a whole, our findings provide a basis to unravel the functions of tau in the ENS and to further investigate the possibility of pathological changes in enteric neuropathies and tauopathies.

A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by beta-amyloid (Aβ) accumulation, phosphorylated tau (p-tau) formation, hyper-activation of glial cells, and neuronal loss. The mechanisms of AD pathogenesis, however, remain poorly understood partially due to the lack of relevant human models that can comprehensively recapitulate multistage-intercellular interactions in human AD brains. Here, we present a new 3D human AD tri-culture model by using neurons, astrocytes, and microglia in a 3D microfluidic platform (3D hNeuroGliAD). Our model provided key representative AD features: Aβ aggregation, p-tau accumulation and neuroinflammatory activity. In particular, the model mirrored microglial recruitment, neurotoxic activities such as axonal cleavage and NO release damaging AD neurons and astrocytes. Our model will serve to facilitate the development of more precise human brain models for basic mechanistic studies in neural-glial interactions and drug discovery.

Escitalopram alleviates stress-induced Alzheimer's disease-liketaupathologies and cognitive deficits by reducing hypothalamic-pituitary-adrenal axis reactivity and insulin/GSK-3βsignal pathway activity.

Chronic stress, a causal factor for depression, can also cause cognitive impairments and tau pathology. However, whether and how the selective serotonin reuptake inhibitor antidepressant escitalopram ameliorates these effects are still unclear. In the present study, rats were subjected to chronic mild unpredictable stress for 8 weeks. Following the initial 4 weeks, the stressed animals were separated into susceptible (depressive) and unsusceptible (resistant) groups based on behavioral tests. Then, escitalopram (10mg/kg i.p.) was administered for 28days. Pathophysiological changes were assessed by performing behavioral and biochemical analyses. The results showed that both depressive and resistant rats displayed spatial memory deficits and an accumulation of tau in the hippocampus. Increased levels of corticosterone and insulin and a decreased level of glucocorticoid receptor were found in both depressive and resistant rats. We also found that activity-dependent phosphorylated insulin receptor substrate and glycogen synthase kinase-3β (Ser9 site) were significantly decreased in both depressive and resistant rats. However, other important kinases, such as cyclin-dependent kinase 5 and mitogen-activated protein kinase kinase-1/2, did not change in our study. Furthermore, we found that the mRNA expression of tau was increased in depressive and resistant rats. No significant change in LC3B expression was found. Interestingly, almost all the pathological changes in depressive and resistant rats previously mentioned could be reversed by escitalopram. Our results suggested that escitalopram ameliorates cognitive impairments and selectively attenuates phosphorylated tau accumulation in stressed rats through the regulation of hypothalamic-pituitary-adrenal axis activity and the insulin receptor substrate/glycogen synthase kinase-3β signaling pathway.

A novel GLP‐1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg-AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-β (Aβ) and phosphorylated tau aggregates, and upregulated the expression levels of S133 p-CREB, T286 p-CAMKII and S9 p-GSK3β in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD.

Tau ablation in mice leads to pancreatic β cell dysfunction and glucose intolerance

The microtubule-associated protein tau is highly expressed in pancreatic islets. Abnormally phosphorylated tau aggregates assemble into neurofibrillary tangles linked to Alzheimer's disease pathology and has also been found in islets of patients with type 2 diabetes. However, the significance of tau in islet function remains relatively unexplored. Therefore, we investigated the role of tau on β cell function and glucose homeostasis using tau knockout (tauKO) mice. TauKO mice were hyperglycemic and glucose intolerant at an early age. Islet insulin content was reduced and proinsulin levels were significantly elevated in tauKO mice, resulting in impaired glucose-stimulated insulin secretion. Loss of tau also resulted in increased epididymal fat mass and leptin levels, reduced glucose production, and insulin resistance at later ages, leading to complete onset of diabetes. Transgenic expression of human tau in islets was unable to rescue those defects in glucose regulation, indicating structural and/or functional differences between mouse and human tau. Cumulatively, these results suggest an important role for tau in the proper maintenance of pancreatic β cell function and glucose homeostasis.-Wijesekara, N., Gonçalves, R. A., Ahrens, R., De Felice, F. G., Fraser, P. E. Tau ablation in mice leads to pancreatic β cell dysfunction and glucose intolerance.

Absence of Neuropathology With Prolonged Isoflurane Sedation in Healthy Adult Rats.

The use of isoflurane sedation for prolonged periods in the critical care environment is increasing. However, isoflurane-mediated neurotoxicity has been widely reported. The goal of the present study was to determine whether long-term exposure to low-dose isoflurane in mechanically ventilated rodents is associated with evidence of neurodegeneration or neuroinflammation. Adult female Sprague-Dawley rats were used in this study. Experimental animals (n=11) were induced with 1.5% isoflurane, intubated, and given a neuromuscular blockade with α-cobratoxin. EEG electrodes were surgically implanted, subcutaneous precordial EKG Ag wire electrodes, and bladder, femoral artery, and femoral vein cannulas permanently placed. After these procedures, the isoflurane concentration was reduced to 0.5% and, in conjunction with the neuromuscular blockade, continued for 7 days. Arterial blood gases and chemistry were measured at 3 time points and core body temperature servoregulated and maintenance IV fluids were given during the 7 days. Experimental animals and untreated controls (n=9) were euthanized on day 7. Immunohistochemical and cytochemical assays did not detect evidence of microgliosis, astrocytosis, neuronal apoptosis or necrosis, amyloidosis, or phosphorylated-tau accumulation. Blood glucose levels were significantly reduced on days 3/4 and 6/7 and partial pressure of oxygen was significantly reduced, but still within the normal range, on day 6/7. All other blood measurements were unchanged. No neuropathologic changes consistent with neurotoxicity were detected in the brain after 1 week of continuous exposure to 0.5% isoflurane in healthy rats. These data suggest that even long exposures to low concentrations of isoflurane have no overt consequences on neuropathology.

Pimozide reduces toxic forms of tau in TauC3 mice via 5' adenosine monophosphate-activated protein kinase-mediated autophagy.

In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease-associated proteins and is often altered in patients and animal models of AD. Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects. Therefore, autophagy activation mediated by non-mTOR pathways is a new option for autophagy-based AD therapy. Here, we report that pimozide activates autophagy to rescue tau pathology in an AD model. Pimozide increased autophagic flux through the activation of the AMPK-Unc-51 like autophagy activating kinase 1 (ULK1) axis, but not of mTOR, in neuronal cells, and this function was independent of dopamine D2 receptor inhibition. Pimozide reduced levels of abnormally phosphorylated tau aggregates in neuronal cells. Further, daily intraperitoneal (i.p.) treatment of pimozide led to a recovery from memory deficits of TauC3 mice expressing a caspase-cleaved form of tau. In the brains of these mice, we found increased phosphorylation of AMPK1 and ULK1, and reduced levels of the soluble oligomers and NP40-insoluble aggregates of abnormally phosphorylated tau. Together, these results suggest that pimozide rescues memory impairments in TauC3 mice and reduces tau aggregates by increasing autophagic flux through the mTOR-independent AMPK-ULK1 axis.

Hippocampal Aβ expression, but not phosphorylated tau, predicts cognitive deficits following repeated peripheral poly I:C administration

Alzheimer’s disease is marked by the accumulation of the amyloid-beta (Aβ) peptide, and increases in phosphorylation of the microtubule associated protein, tau. Changes in these proteins are considered responsible, in part, for the progressive neuronal degeneration and cognitive deficits seen in AD. We examined the effect of repeated consecutive peripheral poly I:C injections on cognitive deficits, central Aβ, and phosphorylated tau accumulation, following three treatment durations: 7, 14, and 21 days. Forty-eight hours after the final injection, animals were trained in a contextual fear-conditioning paradigm, and tested 24h later. Immediately after testing, the hippocampus was collected to quantify Aβ and phosphorylated tau accumulation. Results showed that, although poly I:C-induced Aβ was significantly elevated at all time points examined, poly I:C only disrupted cognition after 14 and 21 days of administration. Moreover, elevations in phosphorylated tau were not seen until the 14-day time point. Interestingly, phosphorylated tau expression then declined at the 21-day time point. Finally, we demonstrated that Aβ levels are a stronger predictor of cognitive dysfunction, explaining 37% of the variance, whereas phosphorylated tau levels only accounted for 0.2%. Taken together, these results support the hypothesis that inflammation-induced elevation in Aβ disrupts cognition, independently of phosphorylated tau, and suggest that long-term administration of poly I:C may provide a model to investigate the contribution of long-term inflammation toward the development of Alzheimer’s-like pathology.

Amyloid beta deposition and phosphorylated tau accumulation are key features in aged choroidal vessels in the complement factor H knock out model of retinal degeneration

Extra-cellular deposition including amyloid beta (Aβ) is a feature of retinal ageing. It has been documented for Bruch’s membrane (BM) where Aβ is elevated in complement factor H knockout mice (Cfh−/−) proposed as a model for age related macular degeneration. However, arterial deposition in choroidal vessels prior to perfusion across BM has not been examined. Aβ is associated with tau phosphorylation and these are linked in blood vessels in Alzheimers Disease where they can drive perivascular pathology. Here we ask if Aβ, tau and phosphorylated tau are features of ageing in choroidal vessels in 12 month C57 BL/6 and Cfh−/− mice, using immune staining and Western blot analysis.Greater levels of Aβ and phosphorylated tau are found in choroidal vessels in Cfh−/− mice. Western blot revealed a 40% increase in Aβ in Cfh−/− over C57 BL/6 mice. Aβ deposits coat around 55% of the luminal wall in Cfh−/− compared to only about 40% in C57 BL/6. Total tau was similar in both groups, but phosphorylated tau increased by >100% in Cfh−/− compared to C57 BL/6 and covered >75% of the luminal wall compared to 50% in C57 BL/6. Hence, phosphorylated tau is a marked choroidal feature in this mouse model. Aβ deposition was clumped in Cfh−/− mice and likely to influence blood flow dynamics. Disturbed flow is associated with atherogenesis and may be related to the accumulation of membrane attack complex recently identified between choroidal vessels in those at high risk of macular degeneration due to complement factor H polymorphisms.

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aβ and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Aβ and p-tau in large populations of individual synaptic terminals. Soluble Aβ oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Aβ was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Aβ oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Aβ-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Aβ drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.