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Abstract Preclinical methods are needed for screening potential Alzheimer’s disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI) stage or even before this stage of the disease. This would require a phenotypic system that reproduces cognitive deficits without significant neuronal cell death to mimic the clinical manifestations of AD during these stages. Long-term potentiation (LTP), which is a correlate of learning and memory, was induced in mature human iPSC-derived cortical neurons cultured on microelectrode arrays utilizing circuit patterns connecting two adjacent electrodes. We demonstrated an LTP system that modeled the MCI and pre-MCI stages of Alzheimer’s and validated this functional system utilizing four AD therapeutics, which was also verified utilizing patch-clamp electrophysiology. LTP was induced by tetanic electrical stimulation, and LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aβ42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aβ42-induced LTP impairment. The results illustrate the utility of the system as a validated platform to model MCI AD pathology, and potentially for the pre-MCI phase before significant neuronal death. This system also has the potential to become an ideal platform for high-content therapeutic screening for other neurodegenerative diseases.

To decipher the evolution of the hominoid brain and its functions, it is essential to conduct comparative studies in primates, including our closest living relatives. However, strong ethical concerns preclude in vivo neuroimaging of great apes. We propose a responsible and multidisciplinary alternative approach that links behavior to brain anatomy in non-human primates from diverse ecological backgrounds. The brains of primates observed in the wild or in captivity are extracted and fixed shortly after natural death, and then studied using advanced MRI neuroimaging and histology to reveal macro- and microstructures. By linking detailed neuroanatomy with observed behavior within and across primate species, our approach provides new perspectives on brain evolution. Combined with endocranial brain imprints extracted from computed tomographic scans of the skulls these data provide a framework for decoding evolutionary changes in hominin fossils. This approach is poised to become a key resource for investigating the evolution and functional differentiation of hominoid brains.

Microtremor seismic surveys are routinely used to provide shear wave velocities that are converted to soil stiffness site profiles. In this paper, we look to assess the feasibility of using trains as seismic sources to characterize near-surface geology, define the optimum survey parameters to collect train-induced vibrations (i.e., array location and orientation to the railway) and find how the geology affects train-induced vibration characteristics. Three-component train-induced shear wave vibrations were recorded on short (44 m) and long (115 m) linear seismic arrays, both parallel and orthogonal to the nearby railway embankment, using standard seismic refraction recording equipment. The collected data were divided into short/long array size/orientation and seismic components for each survey configuration. 1D shear wave velocity-depth profiles were also generated for all data sets. Results showed thst long linear arrays with vertical components, parallel to the railway embankment, was optimal with the greater depth ranges. The vertical component amplitude of train-induced vibrations was found to be affected by the site geology, increasing with the thickening of Quaternary deposits and having different magnitudes for trains traveling in different directions. Results showed that different apparent shear-wave velocities were obtained from different train groups and different seismic components. The passenger trains (i.e. Virgin Trains Pendolino and British Midland 319 series) generate Rayleigh waves at higher frequencies than the freight trains.

This study represents the first attempt to map the sediment thickness spatial distribution along the Andalusian coastal zone by integrating various publicly available datasets. While prior studies have presented bedform- and sediment-type syntheses, none have attempted to quantify sediment thickness at the scale and resolution performed in this study. The study area has been divided into 18 physiographic zones, and we have used BGS Groundhog Desktop v2.6 software for 3D modeling and sediment thickness model calculations. We present here the modeling workflow, model results, and the challenges that we have encountered, including discrepancies in geological maps, difficulty managing data input for grain size/consolidation, and the need for additional geological information. We have compared the modeled sediment fractions of the unconsolidated material with 4194 seabed samples distributed along the study area and found that the differences between the modeled versus the sampled emphasized the importance of incorporating river contributions, particularly from the Guadalquivir River, into the model for more accurate results. The model intermediate and final outputs and the software routines used to query the sediment thickness model are provided as publicly accessible datasets and tools. The modeled sediment thickness could contribute to making quantitative predictions of morphological change at a scale that is relevant to longer-term strategic coastal management in Andalusia. The methodology and tools used for this study are transferable to any study area.

Abstract Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. While these symptoms arise acutely during the course of infection, less is known about the possible long-term consequences for the brain. Severely affected COVID-19 cases experience high levels of proinflammatory cytokines and acute respiratory dysfunction and often require assisted ventilation. All these factors have been suggested to cause cognitive decline. Pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. This article summarizes the current understanding of neurological symptoms of COVID-19 and hypothesizes that affected patients may be at higher risk of developing cognitive decline after overcoming the primary COVID-19 infection. A structured prospective evaluation should analyze the likelihood, time course, and severity of cognitive impairment following the COVID-19 pandemic.

Abstract Background Tau stabilizes microtubules; however, in Alzheimer’s disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression. Methods Male and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N 1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology. Results Tau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain. Conclusion These data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.

Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how Arg1 deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how Arg1 deficiency driven by LysM restriction during amyloidosis affects fundamental neurodegenerative pathways at the transcriptome level. By applying several bioinformatic tools and analyses, we found that amyloid-β (Aβ) stimulated transcriptomic signatures in autophagy-related pathways and myeloid cells’ inflammatory response. At the same time, myeloid Arg1 deficiency during amyloidosis promoted gene signatures of lipid metabolism, myelination, and migration of myeloid cells. Focusing on Aβ associated glial transcriptomic signatures, we found myeloid Arg1 deficiency up-regulated glial gene transcripts that positively correlated with Aβ plaque burden. We also observed that Aβ preferentially activated disease-associated microglial signatures to increase phagocytic response, whereas myeloid Arg1 deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper Arg1 function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern Arg1 metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness.

Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1fl/fl and LysMcreTg/+ mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aβ deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis.

Since the end of the last glaciation, the United Kingdom’s land surface has been altered by isostatic rebound, rising in the north and sinking in the south. Numerous studies have been published documenting the impact of isostatic rebound on relative sea levels. However, due to the difficulties in acquiring evidence to prove former sea levels, locally, these data can be sparse or absent. In this work, we explored the suitability of the passive seismic survey (PSS) method to estimate the contemporaneous beach thickness in coastal environments where there is a high impedance contrast between the beach deposits and the underlying wave-cut platform. We conducted a three-day survey at Perran Beach, Cornwall, collected 149 measurements using PSS, and interpreted the observations supported by auxiliary topographical, geological, and independent geophysical observation in the study area. The study site is a contemporaneous beach mostly composed of sand underlain by a wave-cut platform composed of igneous and sedimentary rock, therefore high impedance contrast with the sandy beach is anticipated. The elevation of the bedrock relative to the topographical elevation suggests that the bedrock elevation is −15 m ± 5 m below the present day mean sea level, which is coherent with the observation of relative sea level rise along the region of the south-west. The present study contributes to our current limited understanding of land and sea level movements by providing further subsurface information to the coastal geological archive of south-west England, a region currently in need of more data to reconstruct land- and sea-level movements.

Innate immune activation is a major contributor to Alzheimer's Disease (AD) pathophysiology, although the mechanisms involved are poorly understood. Chemokine C-C motif ligand (CCL) 2 is produced by neurons and glial cells and is upregulated in the AD brain. Transgene expression of CCL2 in mouse models of amyloidosis produces microglia-induced amyloid β oligomerization, a strong indication of the role of these activation pathways in the amyloidogenic processes of AD. We have previously shown that CCL2 polarizes microglia in wild type mice. However, how CCL2 signaling contributes to tau pathogenesis remains unknown. To address this question, CCL2 was delivered via recombinant adeno-associated virus serotype 9 into both cortex and hippocampus of a mouse model with tau pathology (rTg4510). We report that CCL2 overexpression aggravated tau pathology in rTg4510 as shown by the increase in Gallyas stained neurofibrillary tangles as well as phosphorylated tau-positive inclusions. In addition, biochemical analysis showed a reduction in the levels of detergent-soluble tau species followed by increase in the insoluble fraction, indicating a shift toward larger tau aggregates. Indeed, increased levels of high molecular weight species of phosphorylated tau were found in the mice injected with CCL2. We also report that worsening of tau pathology following CCL2 overexpression was accompanied by a distinct inflammatory response. We report an increase in leukocyte common antigen (CD45) and Cluster of differentiation 68 (CD68) expression in the brain of rTg4510 mice without altering the expression levels of a cell-surface protein Transmembrane Protein 119 (Tmem119) and ionized calcium-binding adaptor molecule 1 (Iba-1) in resident microglia. Furthermore, the analysis of cytokines in brain extract showed a significant increase in interleukin (IL)-6 and CCL3, while CCL5 levels were decreased in CCL2 mice. No changes were observed in IL-1α, IL-1β, TNF-α. IL-4, Vascular endothelial growth factor-VEGF, IL-13 and CCL11. Taken together our data report for the first time that overexpression of CCL2 promotes the increase of pathogenic tau species and is associated with glial neuroinflammatory changes that are deleterious. We propose that these events may contribute to the pathogenesis of Alzheimer's disease and other tauopathies.

Aβ-induced neurodegeneration is limited in APP and APP+PS1 transgenic mice. In middle-aged APP+PS1 transgenic mice, we found significantly increased Bcl-2 expression. The increase in Bcl-2 is restricted to amyloid-containing brain regions and is not found at young ages, suggesting that Aβ deposition is the stimulus for increased Bcl-2. Western blot results were confirmed with immunohistochemistry and qRT-PCR. In addition, we found that APP transgenic mice were protected from neurotoxicity caused by an injection of bak BH3 fusion peptides, known to induce apoptosis by antagonizing bcl protein activity. Nissl and fluorojade-stained slides showed that the active bak BH3 peptide caused substantial neuronal loss in the dentate gyrus and CA3 regions of nontransgenic, but not APP mice. The inactive mutant bak BH3 peptide did not cause degeneration in any mice. These data demonstrate that the increased Bcl-2 expression in brain regions containing Aβ deposits is associated with neuroprotection.

The mechanisms by which anti-Aβ antibodies clear amyloid plaques in Aβ depositing transgenic mice are unclear. In the current study, we demonstrate that inhibition of anti-Aβ antibody-induced microglial activation with anti-inflammatory drugs, such as dexamethasone, inhibits removal of fibrillar amyloid deposits. We also show that anti-Aβ F(ab′)2 fragments fail to activate microglia and are less efficient in removing fibrillar amyloid than the corresponding complete IgG. Diffuse Aβ deposits are cleared by antibodies under all circumstances. These data suggest that microglial activation is necessary for efficient removal of compact amyloid deposits with immunotherapy. Inhibition of this activation may result in an impaired clinical response to vaccination against Aβ.

The accumulation of β-amyloid peptides in the brain has been recognized as an essential factor in Alzheimer's disease pathology. Several proteases, including Neprilysin (NEP), endothelin converting enzyme (ECE), and insulin degrading enzyme (IDE), have been shown to cleave β-amyloid peptides (Aβ). We have previously reported reductions in amyloid in APP+PS1 mice with increased expression of ECE. In this study we compared the vector-induced increased expression of NEP and IDE. We used recombinant adeno-associated viral vectors expressing either native forms of NEP (NEP-n) or IDE (IDE-n), or engineered secreted forms of NEP (NEP-s) or IDE (IDE-s). In a six-week study, immunohistochemistry staining for total Aβ was significantly decreased in animals receiving the NEP-n and NEP-s but not for IDE-n or IDE-s in either the hippocampus or cortex. Congo red staining followed a similar trend revealing significant decreases in the hippocampus and the cortex for NEP-n and NEP-s treatment groups. Our results indicate that while rAAV-IDE does not have the same therapeutic potential as rAAV-NEP, rAAV-NEP-s and NEP-n are effective at reducing amyloid loads, and both of these vectors continue to have significant effects nine months post-injection. As such, they may be considered reasonable candidates for gene therapy trials in AD.

Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer's disease (AD) patients present an energy imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs), widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition) and Tg4510 (a model of tau deposition) mice were offered either a ketogenic or a control (NIH-31) diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition.

While the presence of an inflammatory response in AD (Alzheimer's disease) is well known, the data on inflammation are conflicting, suggesting that inflammation either attenuates pathology, exacerbates it or has no effect. Our goal was to more fully characterize the inflammatory response in APP (amyloid precursor protein) transgenic mice with and without disease progression. In addition, we have examined how anti-A β (amyloid β -peptide) immunotherapy alters this inflammatory response. We have used quantitative RT–PCR (reverse transcription–PCR) and protein analysis to measure inflammatory responses ranging from proinflammatory to anti-inflammatory and repair factors in transgenic mice that develop amyloid deposits only (APPSw) and amyloid deposits with progression to tau pathology and neuron loss [APPSw/NOS2 –/– (nitric oxide synthase 2 –/– )]. We also examined tissues from previously published immunotherapy studies. These studies were a passive immunization study in APPSw mice and an active vaccination study in APPSw/NOS2 –/– mice. Both studies have already been shown to lower amyloid load and improve cognition. We have found that amyloid deposition is associated with high expression of alternative activation and acquired deactivation genes and low expression of pro-inflammatory genes, whereas disease progression is associated with a mixed phenotype including increased levels of some classical activation factors. Immunotherapy targeting amyloid deposition in both mouse models resulted in decreased alternative inflammatory markers and, in the case of passive immunization, a transient increase in pro-inflammatory markers. Our results suggest that an alternative immune response favours retention of amyloid deposits in the brain, and switching away from this state by immunotherapy permits removal of amyloid.

Previous studies have shown that 17,19,21-tri-N-methyl-Aβ16-22 peptide (Aβ16-22m), and a peptide analogue containing α,α-disubsituted amino acids (ααAA) in the hydrophobic core domain of Aβ, termed AMY-1, effectively inhibited full-length Aβ aggregation in vitro. To investigate the amyloid-modifying effects of these agents in vivo, we injected these compounds into the hippocampus of 13-month-old amyloid precursor protein (APP) transgenic mice, a model of amyloid deposition. After 7 days, brain tissues were stained for immunohistochemistry to detect total Aβ and thioflavine-S (THIO-S) to measure Aβ compact plaques. Both diffuse Aβ deposits and compact amyloid plaques were significantly increased when injecting 0.3 nmol Aβ16-22m compared to the PBS vehicle. The amyloid aggregation-modifying peptide AMY-1 showed a slight reduction of Aβ deposition in the injection area at a dose of 0.3 nmol, but neuronal toxicity, measured by Fluoro-Jade and Nissl stains, appeared when higher doses (3 nmol) were tested. Our data indicate that, unlike observations reported in vitro, the Aβ16-22m increased deposition of Aβ in the brain of APP transgenic mice in vivo. Possible explanations for this outcome include unique influences of the brain environment and/or modification of Aβ production or clearance by the administered agent. The AMY-1 peptide showed a trend for reducing Aβ deposits, but led to toxicity at higher doses. These data emphasize the need for evaluating potential Aβ aggregation inhibitors with in vivo models of amyloid deposition before assuming they will have benefit in treating Alzheimer's disease patients.