Chaperones safeguard protein homeostasis by promoting folding and preventing aggregation. HSP110 is a cytosolic chaperone that functions as a nucleotide exchange factor for the HSP70 cycle. Together with HSP70 and a J-domain protein (JDP), HSP110 maintains protein folding and resolubilizes aggregates. Interestingly, HSP110 is vital for the HSP70/110/JDP-mediated disaggregation of amyloidogenic proteins implicated in neurodegenerative diseases (i.e., α-synuclein, HTT, and tau). However, despite its abundance, HSP110 remains still an enigmatic chaperone, and its functional spectrum is not very well understood. Of note, the disaggregation activity of neurodegenerative disease-associated amyloid fibrils showed both beneficial and detrimental outcomes in vivo. To gain a more comprehensive understanding of the chaperone HSP110 in vivo, we analyzed its role in neuronal proteostasis and neurodegeneration in C. elegans. Specifically, we investigated the role of HSP110 in the regulation of amyloid beta peptide (Aβ) aggregation using an established Aβ-C. elegans model that mimics Alzheimer\'s disease pathology. We generated a novel C. elegans model that over-expresses hsp-110 pan-neuronally, and we also depleted hsp-110 by RNAi-mediated knockdown. We assessed Aβ aggregation in vivo and in situ by fluorescence lifetime imaging. We found that hsp-110 over-expression exacerbated Aβ aggregation and appeared to reduce the conformational variability of the Aβ aggregates, whereas hsp-110 depletion reduced aggregation more significantly in the IL2 neurons, which marked the onset of Aβ aggregation. HSP-110 also plays a central role in growth and fertility as its over-expression compromises nematode physiology. In addition, we found that HSP-110 modulation affects the autophagy pathway. While hsp-110 over-expression impairs the autophagic flux, a depletion enhances it. Thus, HSP-110 regulates multiple nodes of the proteostasis network to control amyloid protein aggregation, disaggregation, and autophagic clearance.

Clearance of amyloid-beta (Aβ) from the brain is impaired in both early-onset and late-onset Alzheimer\'s disease (AD). Mechanisms for clearing cerebral Aβ include proteolytic degradation, antibody-mediated clearance, blood brain barrier and blood cerebrospinal fluid barrier efflux, glymphatic drainage, and perivascular drainage. ATP-binding cassette (ABC) transporters are membrane efflux pumps driven by ATP hydrolysis. Their functions include maintenance of brain homeostasis by removing toxic peptides and compounds, and transport of bioactive molecules including cholesterol. Some ABC transporters contribute to lowering of cerebral Aβ. Mechanisms suggested for ABC transporter-mediated lowering of brain Aβ, in addition to exporting of Aβ across the blood brain and blood cerebrospinal fluid barriers, include apolipoprotein E lipidation, microglial activation, decreased amyloidogenic processing of amyloid precursor protein, and restricting the entrance of Aβ into the brain. The ABC transporter superfamily in humans includes 49 proteins, eight of which have been suggested to reduce cerebral Aβ levels. This review discusses experimental approaches for increasing the expression of these ABC transporters, clinical applications of these approaches, changes in the expression and/or activity of these transporters in AD and transgenic mouse models of AD, and findings in the few clinical trials which have examined the effects of these approaches in patients with AD or mild cognitive impairment. The possibility that therapeutic upregulation of ABC transporters which promote clearance of cerebral Aβ may slow the clinical progression of AD merits further consideration.

A major hallmark of Alzheimer\'s disease is the accumulation of aggregated amyloid β peptide (Aβ) in the brain. Here we develop a solubility assay for proteins and measure the solubility of Aβ40. In brief, the method utilizes 96-well filter plates to separate monomeric Aβ from aggregated Aβ, and the small species are quantified with the amine reactive dye o-phthalaldehyde (OPA). This procedure ensures that solubility is measured for unlabeled species, and makes the assay high-throughput and inexpensive. We demonstrate that the filter plates successfully separate fibrils from monomer, with negligible monomer adsorption, and that OPA can quantify Aβ peptides in a concentration range from 40 nM to 20 μM. We also show that adding a methionine residue to the N-terminus of Aβ1-40 decreases the solubility by <3-fold. The method will facilitate further solubility studies, and contribute to the understanding of the thermodynamics of amyloid fibril formation.

We identified a sub-group (25%) of people with schizophrenia (muscarinic receptor deficit schizophrenia (MRDS)) that are characterised because of markedly lower levels of cortical muscarinic M1 receptors (CHRM1) compared to most people with the disorder (non-MRDS). Notably, bioinformatic analyses of our cortical gene expression data shows a disturbance in the homeostasis of a biochemical pathway that regulates levels of CHRM1. A step in this pathway is the processing of β-amyloid precursor protein (APP) and therefore we postulated there would be altered levels of APP in the frontal cortex from people with MRDS. Here we measure levels of CHRM1 using [3H]pirenzepine binding, soluble APP (sAPP) using Western blotting and amyloid beta peptides (Aβ1-40 and Aβ1-42) using ELISA in the frontal cortex (Brodmann\'s area 6: BA 6; MRDS = 14, non-MRDS = 14, controls = 14). We confirmed the MRDS cohort in this study had the expected low levels of [3H]pirenzepine binding. In addition, we showed that people with schizophrenia, independent of their sub-group status, had lower levels of sAPP compared to controls but did not have altered levels of Aβ1-40 or Aβ1-42. In conclusion, whilst changes in sAPP are not restricted to MRDS our data could indicate a role of APP, which is important in axonal and synaptic pruning, in the molecular pathology of the syndrome of schizophrenia.

UNASSIGNED: Post-operative cognitive dysfunction (POCD) is a common central nervous system complication after surgery. Inhaled anesthetic sevoflurane is thought to have harmful effects on the developing and aged nerves, but its effects on adults\' nervous system are less studied and the mechanism is not clear.
UNASSIGNED: Male adult rats were divided into control group and sevoflurane group. Rats from sevoflurane group were received 3.2% sevoflurane + carrier gas (1 L/min O2+1 L/min air) for 2 h, while control group received carrier gas for 2 h. Each group was subsequently divided into 3 subgroups according to the Day 1, Day 3, Day 7 after sevoflurane anesthesia. Morris Water Maze, amyloid-beita (Abeta) and apolipoprotein E (ApoE) mRNA in hippocampus were analyzed. Then, adult ApoE-/- rats were also divided into control group and sevoflurane group. Each group was divided into 3 subgroups according to Day 1, Day 3 and Day 7. Abeta mRNA and protein expression in hippocampus were analyzed.
UNASSIGNED: Compared with the control group, hippocampal Abeta mRNA and protein expression in rats from sevoflurane group significantly increased in hippocampus on Day 7, while ApoE mRNA and protein expression increased on Day 1 and Day 3. There was no difference in times of crossing platforms, time during platform, times across platform quadrant and time percent during platform quadrant between each group. Compared with the control group, hippocampal Abeta and ApoE-/- rats in sevoflurane group did not change.
UNASSIGNED: ApoE modulates hippocampal Abeta deposition and stabilizes learning and memory ability in adult rats after sevoflurane exposure, but this effect is not constant.

UNASSIGNED: People with DS are highly predisposed to Alzheimer\'s disease (AD) and demonstrate very similar clinical and pathological features. Ts65Dn mice are widely used and serve as the best-characterized animal model of DS.
UNASSIGNED: We undertook studies to characterize age-related changes for AD-relevant markers linked to Aβ, Tau, and phospho-Tau, axonal structure, inflammation, and behavior.
UNASSIGNED: We found age related changes in both Ts65Dn and 2N mice. Relative to 2N mice, Ts65Dn mice showed consistent increases in Aβ40, insoluble phospho-Tau, and neurofilament light protein. These changes were correlated with deficits in learning and memory.
UNASSIGNED: These data have implications for planning future experiments aimed at preventing disease-related phenotypes and biomarkers. Interventions should be planned to address specific manifestations using treatments and treatment durations adequate to engage targets to prevent the emergence of phenotypes.

Alzheimer\'s disease (AD) is a rapidly growing disease that affects millions of people worldwide, therefore there is an urgent need for its early diagnosis and treatment. A huge amount of research studies are performed on possible accurate and reliable diagnostic biomarkers of AD. Due to its direct contact with extracellular space of the brain, cerebrospinal fluid (CSF) is the most useful biological fluid reflecting molecular events in the brain. Proteins and molecules that reflect the pathogenesis of the disease, e.g., neurodegeneration, accumulation of Abeta, hyperphosphorylation of tau protein and apoptosis may be used as biomarkers. The aim of the current manuscript is to present the most commonly used CSF biomarkers for AD as well as novel biomarkers. Three CSF biomarkers, namely total tau, phospho-tau and Abeta42, are believed to have the highest diagnostic accuracy for early AD diagnosis and the ability to predict AD development in mild cognitive impairment (MCI) patients. Moreover, other biomarkers such as soluble amyloid precursor protein (APP), apoptotic proteins, secretases and inflammatory and oxidation markers are believed to have increased future prospects.

The key pathologic entities driving the destruction of synaptic function and integrity during the evolution of Alzheimer\'s disease (AD) remain elusive. Astrocytes are structurally and functionally integrated within synaptic and vascular circuitry and use calcium-based physiology to modulate basal synaptic transmission, vascular dynamics, and neurovascular coupling, which are central to AD pathogenesis. We used high-resolution multiphoton imaging to quantify all endogenous calcium signaling arising spontaneously throughout astrocytic somata, primary processes, fine processes, and capillary endfeet in the brain of awake APP/PS1 transgenic mice (11 male and 6 female mice). Endogenous calcium signaling within capillary endfeet, while surprisingly as active as astrocytic fine processes, was reduced ∼50% in the brain of awake APP/PS1 mice. Cortical astrocytes, in the presence of amyloid plaques in awake APP/PS1 mice, had a cell-wide increase in intracellular calcium associated with an increased frequency, amplitude, and duration of spontaneous calcium signaling. The cell-wide astrocytic calcium dysregulation was not directly related to distance to amyloid plaques. We could re-create the cell-wide intracellular calcium dysregulation in the absence of amyloid plaques following acute exposure to neuronally derived soluble Abeta from Tg2576 transgenic mice, in the living brain of male C57/Bl6 mice. Our findings highlight a role for astrocytic calcium pathophysiology in soluble-Abeta mediated neurodegenerative processes in AD. Additionally, therapeutic strategies aiming to protect astrocytic calcium physiology from soluble Abeta-mediated toxicity may need to pharmacologically enhance calcium signaling within the hypoactive capillary endfeet while reducing the hyperactivity of spontaneous calcium signaling throughout the rest of the astrocyte.SIGNIFICANCE STATEMENT Astrocytic calcium signaling is functionally involved in central pathologic processes of Alzheimer\'s disease. We quantified endogenous calcium signaling arising spontaneously in the brain of awake APP/PS1 mice, as general anesthesia suppressed astrocytic calcium signaling. Cell-wide astrocytic calcium dysregulation was not related to distance to amyloid plaques but mediated in part by neuronally derived soluble Abeta, supporting a role for astrocytes in soluble-Abeta mediated neurodegeneration. Spontaneous calcium signaling is largely compartmentalized and capillary endfeet were as active as fine processes but hypoactive in the presence of amyloid plaques, while the rest of the astrocyte became hyperactive. The cell-wide calcium pathophysiology in astrocytes may require a combination therapeutic strategy for hypoactive endfeet and astrocytic hyperactivity.

Senile plaques consisting of amyloid-beta (Aβ) peptides are a major pathological hallmark of Alzheimer\'s disease (AD). Aβ peptides are heterogeneous regarding the exact length of their amino- and carboxy-termini. Aβ1-40 and Aβ1-42 are often considered to represent canonical \"full-length\" Aβ species. Using immunohistochemistry, we analyzed the distribution of Aβ1-x, Aβx-42 and Aβ4-x species in amyloid deposits in the subiculum, hippocampus and cortex in 5XFAD mice during aging. Overall plaque load increased in all three brain regions, with the subiculum being the area with the strongest relative plaque coverage. In the subiculum, but not in the other brain regions, the Aβ1-x load peaked at an age of five months and decreased thereafter. In contrast, the density of plaques positive for N-terminally truncated Aβ4-x species increased continuously over time. We hypothesize that ongoing plaque remodeling takes place, leading to a conversion of deposited Aβ1-x peptides into Aβ4-x peptides in brain regions with a high Aβ plaque burden.

The accumulation of pathogenic protein oligomers and aggregates is associated with several devastating amyloid diseases. As protein aggregation is a multi-step nucleation-dependent process beginning with unfolding or misfolding of the native state, it is important to understand how innate protein dynamics influence aggregation propensity. Kinetic intermediates composed of heterogeneous ensembles of oligomers are frequently formed on the aggregation pathway. Characterization of the structure and dynamics of these intermediates is critical to the understanding of amyloid diseases since oligomers appear to be the main cytotoxic agents. In this review, we highlight recent biophysical studies of the roles of protein dynamics in driving pathogenic protein aggregation, yielding new mechanistic insights that can be leveraged for design of aggregation inhibitors.