Reactive astrocytes secrete the chaperone HSPB1 to mediate neuroprotection.

Molecular chaperones are protective in neurodegenerative diseases by preventing protein misfolding and aggregation, such as extracellular amyloid plaques and intracellular tau neurofibrillary tangles in Alzheimer's disease (AD). In addition, AD is characterized by an increase in astrocyte reactivity. The chaperone HSPB1 has been proposed as a marker for reactive astrocytes; however, its astrocytic functions in neurodegeneration remain to be elucidated.

P2XR influences tau aggregate burden in human tauopathies and shows distinct signalling in microglia and astrocytes.

The purinoceptor P2XR is a promising therapeutic target for tauopathies, including Alzheimer's disease (AD). Pharmacological inhibition or genetic knockdown of P2XR ameliorates cognitive deficits and reduces pathological tau burden in mice that model aspects of tauopathy, including mice expressing mutant human frontotemporal dementia (FTD)-causing forms of tau. However, disagreements remain over which glial cell types express P2XR and therefore the mechanism of action is unresolved.

Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aβ.

Astrocytes associate with amyloid plaques in Alzheimer's disease (AD). Astrocytes react to changes in the brain environment, including increasing concentrations of amyloid-β (Aβ). However, the precise response of astrocytes to soluble small Aβ oligomers at concentrations similar to those present in the human brain has not been addressed.

Astrocyte adaptation in Alzheimer's disease: a focus on astrocytic P2X7R.

Astrocytes are key homeostatic and defensive cells of the central nervous system (CNS). They undertake numerous functions during development and in adulthood to support and protect the brain through finely regulated communication with other cellular elements of the nervous tissue. In Alzheimer's disease (AD), astrocytes undergo heterogeneous morphological, molecular and functional alterations represented by reactive remodelling, asthenia and loss of function.

Cysteine string protein alpha accumulates with early pre-synaptic dysfunction in Alzheimer's disease.

In Alzheimer's disease, synapse loss causes memory and cognitive impairment. However, the mechanisms underlying synaptic degeneration in Alzheimer's disease are not well understood. In the hippocampus, alterations in the level of cysteine string protein alpha, a molecular co-chaperone at the pre-synaptic terminal, occur prior to reductions in synaptophysin, suggesting that it is a very sensitive marker of synapse degeneration in Alzheimer's.

Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity.

Background: Pathological interactions between β-amyloid (Aβ) and tau drive synapse loss and cognitive decline in Alzheimer's disease (AD). Reactive astrocytes, displaying altered functions, are also a prominent feature of AD brain. This large and heterogeneous population of cells are increasingly recognised as contributing to early phases of disease.

Reactive astrocyte nomenclature, definitions, and future directions.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them.

Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation.

It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice.

Astrocytes in Tauopathies.

Tauopathies are a group of neurodegenerative diseases characterized by the progressive accumulation across the brain of hyperphosphorylated aggregates of the microtubule-associated protein tau that vary in isoform composition, structural conformation and localization. Tau aggregates are most commonly deposited within neurons but can show differential association with astrocytes, depending on the disease. Astrocytes, the most abundant neural cells in the brain, play a major role in synapse and neuronal function, and are a key component of the glymphatic system and blood brain barrier.

Bridging Integrator-1 protein loss in Alzheimer's disease promotes synaptic tau accumulation and disrupts tau release.

Polymorphisms associated with confer the second greatest risk for developing late onset Alzheimer's disease. The biological consequences of this genetic variation are not fully understood, however BIN1 is a binding partner for tau. Tau is normally a highly soluble cytoplasmic protein, but in Alzheimer's disease tau is abnormally phosphorylated and accumulates at synapses to exert synaptotoxicity.

The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity.

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions. This signaling involves close physical contacts between the two organelles that are mediated by "tethering proteins" that function to recruit regions of ER to the mitochondrial surface. The ER protein, vesicle-associated membrane protein-associated protein B (VAPB) and the mitochondrial membrane protein, protein tyrosine phosphatase interacting protein-51 (PTPIP51), interact to form one such tether.

Distinct cytokine profiles in human brains resilient to Alzheimer's pathology.

Our group has previously studied the brains of some unique individuals who are able to tolerate robust amounts of Alzheimer's pathological lesions (amyloid plaques and neurofibrillary tangles) without experiencing dementia while alive. These rare resilient cases do not demonstrate the patterns of neuronal/synaptic loss that are normally found in the brains of typical demented Alzheimer's patients. Moreover, they exhibit decreased astrocyte and microglial activation markers GFAP and CD68, suggesting that a suppressed neuroinflammatory response may be implicated in human brain resilience to Alzheimer's pathology.

Deciphering the Astrocyte Reaction in Alzheimer's Disease.

Reactive astrocytes were identified as a component of amyloid plaques in the cortex of Alzheimer's disease (AD) patients several decades ago. However, their role in AD pathophysiology has remained elusive ever since, in part owing to the extrapolation of the literature from primary astrocyte cultures and acute brain injury models to a chronic neurodegenerative scenario. Recent accumulating evidence supports the idea that reactive astrocytes in AD acquire neurotoxic properties, likely due to both a gain of toxic function and a loss of their neurotrophic effects.

Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer's disease brain.

Alterations in calcium homeostasis are widely reported to contribute to synaptic degeneration and neuronal loss in Alzheimer's disease. Elevated cytosolic calcium concentrations lead to activation of the calcium-sensitive cysteine protease, calpain, which has a number of substrates known to be abnormally regulated in disease. Analysis of human brain has shown that calpain activity is elevated in AD compared to controls, and that calpain-mediated proteolysis regulates the activity of important disease-associated proteins including the tau kinases cyclin-dependent kinase 5 and glycogen kinase synthase-3.

Stress Increases the Negative Effects of Chronic Pain on Hippocampal Neurogenesis.

Background: Patients with chronic pain often suffer from affective disorders and cognitive decline, which significantly impairs their quality of life. In addition, many of these patients also experience stress unrelated to their illness, which can aggravate their symptoms. These nociceptive inputs are received by the hippocampus, in which maladaptive neuroplastic changes may occur in the conditions of chronic pain.

Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology.

Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases.