Early Stages Of Neurodegeneration Research Articles

MRI-informed machine learning-driven brain age models for classifying mild cognitive impairment converters.

Brain age model, including estimated brain age and brain-predicted age difference (brain-PAD), has shown great potentials for serving as imaging markers for monitoring normal ageing, as well as for identifying the individuals in the pre-diagnostic phase of neurodegenerative diseases. This study aimed to investigate the brain age models in normal ageing and mild cognitive impairments (MCI) converters and their values in classifying MCI conversion. Pre-trained brain age model was constructed using the structural magnetic resonance imaging (MRI) data from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) project (N = 609). The tested brain age model was built using the baseline, 1-year and 3-year follow-up MRI data from normal ageing (NA) adults (n = 32) and MCI converters (n = 22) drew from the Open Access Series of Imaging Studies (OASIS-2). The quantitative measures of morphometry included total intracranial volume (TIV), gray matter volume (GMV) and cortical thickness. Brain age models were calculated based on the individual's morphometric features using the support vector machine (SVM) algorithm. With comparable chronological age, MCI converters showed significant increased TIV-based (Baseline: P = 0.021; 1-year follow-up: P = 0.037; 3-year follow-up: P = 0.001) and left GMV-based brain age than NA adults at all time points. Higher brain-PAD scores were associated with worse global cognition. Acceptable classification performance of TIV-based (AUC = 0.698) and left GMV-based brain age (AUC = 0.703) was found, which could differentiate the MCI converters from NA adults at the baseline. This is the first demonstration that MRI-informed brain age models exhibit feature-specific patterns. The greater GMV-based brain age observed in MCI converters may provide new evidence for identifying the individuals at the early stage of neurodegeneration. Our findings added value to existing quantitative imaging markers and might help to improve disease monitoring and accelerate personalized treatments in clinical practice.

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

BackgroundBioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer’s, Parkinson’s, and Huntington’s disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose long-projecting axons are often vulnerable in neurodegenerative conditions. We also tested if NMNAT2 maintains axonal health by ensuring axonal ATP levels for axonal transport, critical for axonal function.MethodsWe generated mouse and cultured neuron models to determine the impact of NMNAT2 loss from cortical glutamatergic neurons on axonal transport, energetic metabolism, and morphological integrity. In addition, we determined if exogenous NAD supplementation or inhibiting a NAD hydrolase, sterile alpha and TIR motif-containing protein 1 (SARM1), prevented axonal deficits caused by NMNAT2 loss. This study used a combination of techniques, including genetics, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, and anti-sense oligos.ResultsWe provide in vivo evidence that NMNAT2 in glutamatergic neurons is required for axonal survival. Using in vivo and in vitro studies, we demonstrate that NMNAT2 maintains the NAD-redox potential to provide “on-board” ATP via glycolysis to vesicular cargos in distal axons. Exogenous NAD+ supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. Finally, we demonstrate both in vitro and in vivo that reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2 KO neurons.ConclusionNMNAT2 ensures axonal health by maintaining NAD redox potential in distal axons to ensure efficient vesicular glycolysis required for fast axonal transport.

Investigating the Prognostic Role of Peripheral Inflammatory Markers in Mild Cognitive Impairment

Growing evidence suggests that neuroinflammation plays a critical role in the pathogenesis of neurodegenerative diseases. Peripheral markers of inflammation, including blood cell counts and their ratios, such as the neutrophil-to-lymphocyte ratio (NLR), have been reported as an easily accessible and reliable proxy of central nervous system inflammation. However, the role of peripheral inflammation in dementia and Mild Cognitive Impairment (MCI) still needs to be clarified. In the current study, we aimed to assess the prognostic role of the NLR and other peripheral markers of inflammation in a sample of 130 amnestic MCI, followed up for two to five years. The Mini-Mental state examination (MMSE) score at baseline and follow-up visits was used to assess global cognitive status at each visit and the degree of cognitive decline over time. Baseline peripheral markers of inflammation included blood cell counts and ratios, specifically the NLR, the platelet-to-lymphocyte ratio (PLR), the monocyte-to-lymphocyte ratio (MLR), and the systemic immune inflammation index (SII). After classifying subjects into CONVERTERS and non-CONVERTERS (respectively, patients converting to dementia and subjects showing stability at the last available follow-up), we compared peripheral markers of inflammation among groups ed correlated them with cognitive measures, testing the ability of significant factors to predict conversion to dementia. In our cohort, CONVERTERS showed lower baseline MMSE scores (p-value = 0.004) than non-CONVERTERS. In addition, CONVERTERS had statistically elevated NLR (p-value = 0.005), PLR (p-value = 0.002), and SII levels (p-value = 0.015), besides a lower number of lymphocytes (p-value = 0.004) compared with non-CONVERTERS. In a logistic regression analysis, baseline MMSE scores and NLR predicted conversion to dementia. Tertiles analysis showed that MCI with the highest NLR values had a higher conversion risk. Our study supports the hypothesis that a dysregulation of peripheral inflammation involving both lymphocytes and neutrophils may play a role in the pathogenesis of dementia, even at the early stages of neurodegeneration, as in the MCI condition.

Age‑related brainstem degeneration through microRNA modulation in mice.

Histopathological changes occur in the brainstem during the early stages of Alzheimer's disease (AD), with the pathological changes of the brain lesions ascending progressively in accordance with the Braak staging system. The senescence‑accelerated mouse prone 8 (SAMP8) mouse model has been previously used as a model of age‑dependent neurodegenerative diseases, including AD. In the present study, microRNAs (miRNAs) that were upregulated or downregulated in SAMP8 brainstems were identified using miRNA profiling of samples obtained from miRNA arrays. The preliminary stage of cognitive dysfunction was examined using male 5‑month‑old SAMP8 mice, with age‑matched senescence‑accelerated mouse resistant 1 mice as controls. A Y‑maze alternation test was performed to assess short‑term working memory and miRNA profiling was performed in each region of the dissected brain (brainstem, hippocampus and cerebral cortex). SAMP8 mice tended to be hyperactive, but short‑term working memory was preserved. Two miRNAs were upregulated (miR‑491‑5p and miR‑764‑5p) and two were downregulated (miR‑30e‑3p and miR‑323‑3p) in SAMP8 brainstems. In SAMP8 mice, the expression level of upregulated miRNAs were the highest in the brainstem, wherein age‑related brain degeneration occurs early. It was demonstrated that the order of specific miRNA expression levels corresponded to the progression order of age‑related brain degeneration. Differentially expressed miRNAs regulate multiple processes, including neuronal cell death and neuron formation. Changes in miRNA expression may result in the induction of target proteins during the early stages of neurodegeneration in the brainstem. These findings suggest that studying altered miRNA expression may provide molecular evidence for early age‑related neuropathological changes.

An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-β (Aβ)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. The early stages of neurodegeneration in AD include the loss of neurons, followed by synaptic impairment. Since the discovery of AD, substantial factual research has surfaced that outlines the disease's causes, molecular mechanisms, and prospective therapeutics, but a successful cure for the disease has not yet been discovered. This may be attributed to the complicated pathogenesis of AD, the absence of a well-defined molecular mechanism, and the constrained diagnostic resources and treatment options. To address the aforementioned challenges, extensive disease modeling is essential to fully comprehend the underlying mechanisms of AD, making it easier to design and develop effective treatment strategies. Emerging evidence over the past few decades supports the critical role of Aβ and tau in AD pathogenesis and the participation of glial cells in different molecular and cellular pathways. This review extensively discusses the current understanding concerning Aβ- and tau-associated molecular mechanisms and glial dysfunction in AD. Moreover, the critical risk factors associated with AD including genetics, aging, environmental variables, lifestyle habits, medical conditions, viral/bacterial infections, and psychiatric factors have been summarized. The present study will entice researchers to more thoroughly comprehend and explore the current status of the molecular mechanism of AD, which may assist in AD drug development in the forthcoming era.

Doxycycline inhibits dopaminergic neurodegeneration through upregulation of axonal and synaptic proteins.

Doxycycline (DOX) is a widely used antibiotic that is able to cross the blood-brain barrier. Several studies have shown its neuroprotective effect against neurodegeneration and have associated it with antioxidant, anti-apoptotic, and anti-inflammatory mechanisms. We have recently demonstrated that DOX mimics nerve growth factor (NGF) signaling in PC12 cells. However, the involvement of this mechanism in the neuroprotective effect of DOX is unknown. Axonal degeneration and synaptic loss are key events at the early stages of neurodegeneration, and precede the neuronal death in neurodegenerative diseases, including Parkinson's disease (PD). Therefore, the regeneration of the axonal and synaptic network might be beneficial in PD. The effect of DOX in PC12 cells treated with the Parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP+) was addressed. Doxycycline reduced the inhibition of neuritogenesis induced by MPP+, even in cells deprived of NGF. The mechanism involved the upregulation of GAP-43, synapsin I, β-III-tubulin, F-actin, and neurofilament-200, proteins that are associated with axonal and synaptic plasticity. Considering the role of axonal degeneration and synaptic loss at the initial stages of PD, the recent advances in early diagnosis of neurodegeneration, and the advantages of drug repurposing, doxycycline is a promising candidate to treat PD.

Neuropsychiatric symptoms, Alzheimer’s Disease and Cerebrospinal Fluid Cortisol and Dehydroepiandrosterone Sulfate: a Prospective Study

AbstractBackgroundNeuropsychiatric symptoms (NPS) are important treatment targets in the management of dementia, can be present at very early stages of neurodegeneration, and are associated with more rapid clinical disease progression. Increased cortisol has been reported in Alzheimer’s disease (AD), and has been associated with cognitive decline. At the same time, cortisol is often referred to as the “stress hormone” and elevated cortisol output has been observed in association with depression and delirium. Dehydroepiandrosterone sulfate (DHEAS) has known anti‐glucocorticoid effects and may counter the effects of cortisol.MethodsOne hundred and twenty‐three participants with cognitive impairment (mild cognitive impairment or dementia, N=78) and with normal cognition (N=53) were included in a prospective study in a memory clinic setting. NPS were assessed using the Neuropsychiatric Inventory (NPI), CSF cortisol and DHEAS, as well as CSF AD biomarkers were obtained at baseline. NPS and cognitive performance were re‐assessed at follow‐up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline NPS, AD pathology, and CSF cortisol and DHEA. We used repeated‐measures mixed ANCOVA models to examine the associations between the NPS changes over time, baseline CSF cortisol and DHEA, and AD pathology.ResultsHigher CSF cortisol was associated with more common (p<0.001) and more severe NPS at baseline after controlling for covariates (B=0.091[0.031;0.150], p=0.003; r=0.309), in particular with depression, anxiety, apathy/indifference. Elevated CSF cortisol was also associated with NPS worsening over time regardless of AD pathology (p=0.036, η2=0.207). Both associations remained significant after controlling for AD pathology status. CSF DHEAS was neither associated with NPS at baseline nor with their change over time.ConclusionElevated CSF cortisol is associated with more severe NPS at baseline, as well as with more pronounced worsening over three years, independently of AD pathology status. Cortisol may predict the course of NPS in individuals with cognitive impairment. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms of dementia.

Is cortical grey matter diffusivity an early biomarker for neuronal damage?

AbstractBackgroundThere is growing evidence that pathological changes in Alzheimer’s disease (AD) begin several years before the symptom onset. Neuroimaging approaches can be used to detect microstructural alterations in the early stages of neurodegeneration using diffusion‐weighted MRI. Cortical grey matter mean diffusivity (cMD) is thought to be increased in AD following pathological alterations resulting in disrupted neuronal function, neuronal death and cellular atrophy. We hypothesised that changes in MD could be detected early in the disease progression and that they would be correlated with structural imaging biomarkers.Method72 patients (mean age=69.1, SD=9.2) cognitively normal (CN, n=21) and with mild cognitive impairment (MCI, n=51) were included in this study. All participants underwent T1‐weighted MPRAGE MRI, diffusion tensor imaging (DTI) and PET amyloid ([18F]flutemetamol). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. DTI data were processed with FSL v.6.0 to compute MD maps. Standard uptake ratio (SUVR) values were calculated in SPM12 to identify the amyloid deposition within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a cerebellar gray matter reference to create target‐to‐cerebellar ratio. Subjects were considered positive with an uptake value of greater than mean+2SD of the control subjects. Student's t‐test were used to compare imaging modalities between CN and MCI participants. Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.ResultThere was a significantly increased MD in MCI compared to CN participants in hippocampus (p=0.0213) and in medial temporal lobe (p=0.033). There were no significant group differences neither in whole brain mean cortical thickness (p=0.6984) nor in temporal cortical thickness (p=0.0923). Interestingly, when splitting subjects based on their amyloid status, we found that whole brain MD was significantly negatively correlated with whole brain cortical thickness in amyloid negative (CN+MCI amyloid negative, p<0.001) but not in amyloid positive (CN+MCI amyloid positive, p=0.99).ConclusionWe found that changes in gray matter diffusivity could be detected in the early stages of AD pathology. We also found that there is a direct relationship between MD and structural changes (i.e. cortical thickness) only before amyloid deposition suggesting that MD provides information about early microstructural changes before macrostructural changes.

A Potential Mechanism for Targeting Aggregates With Proteasomes and Disaggregases in Liquid Droplets.

Insoluble protein deposits are hallmarks of neurodegenerative disorders and common forms of dementia. The aberrant aggregation of misfolded proteins involves a complex cascade of events that occur over time, from the cellular to the clinical phase of neurodegeneration. Declining neuronal health through increased cell stress and loss of protein homeostasis (proteostasis) functions correlate with the accumulation of aggregates. On the cellular level, increasing evidence supports that misfolded proteins may undergo liquid-liquid phase separation (LLPS), which is emerging as an important process to drive protein aggregation. Studying the reverse process of aggregate disassembly and degradation has only recently gained momentum, following reports of enzymes with distinct aggregate-disassembly activities. In this review, we will discuss how the ubiquitin-proteasome system and disaggregation machineries such as VCP/p97 and HSP70 system may disassemble and/or degrade protein aggregates. In addition to their canonically associated functions, these enzymes appear to share a common feature: reversibly assembling into liquid droplets in an LLPS-driven manner. We review the role of LLPS in enhancing the disassembly of aggregates through locally increasing the concentration of these enzymes and their co-proteins together within droplet structures. We propose that such activity may be achieved through the concerted actions of disaggregase machineries, the ubiquitin-proteasome system and their co-proteins, all of which are condensed within transient aggregate-associated droplets (TAADs), ultimately resulting in aggregate clearance. We further speculate that sustained engagement of these enzymatic activities within TAADs will be detrimental to normal cellular functions, where these activities are required. The possibility of facilitating endogenous disaggregation and degradation activities within TAADs potentially represents a novel target for therapeutic intervention to restore protein homeostasis at the early stages of neurodegeneration.

Effects of ketogenic diet on cognitive functions of mice fed high-fat-high-cholesterol diet

Long-term dietary intake of elevated levels of refined sugars, fats and cholesterols is among the factors causing cognitive impairment. Ketone bodies can be used as an alternative energy source when glucose is not available. The study investigated the effects of a ketogenic diet (medium chain triglyceride, MCT) on cognitive performance after a long-term consumption of a high-fat-high-cholesterol diet using a mice model. Seventy eight-week-old male C57BL/6 mice were fed an HFHC diet for 16 weeks to establish a model of an HFHC dietary pattern, before receiving intervention diets containing MCT diet or with Metformin for another 8 weeks in the second part of the experiment. Spatial learning, memory performance, and cortical and hippocampal protein expression levels were assessed. After consuming the HFHC diet for 16 weeks and subsequently receiving the MCT diet for 8 weeks, results showed that the mice fed a MCT diet had significantly better spatial learning and memory performance, lower expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), amyloid protein precursor (APP) and phosphate tau, and higher expression of brain-derived neurotrophic factor (BDNF) than the mice fed the HFHC diet. Long-term consumption of an HFHC diet caused a decline in cognitive functions and increased the risk factors for neurodegeneration, such as BBB permeability, neuropathy and inflammation. An MCT diet can be considered as an option for slowing down the early stage of neurodegeneration in mice.

Oxidative stress-mediated inflammation promotes the pathogenesis of amyotrophic lateral sclerosis

Neuroinflammation in amyotrophic lateral sclerosis (ALS) is characterized by activation of monocytes/macrophages and T lymphocytes in the periphery and microglia and astrocytes within the central nervous system. This review emphasizes the role of oxidative stress in promoting systemic inflammation and the early stages of neurodegeneration. Motor axon terminals of ALS patients have significantly increased intraluminal calcium and dysfunctional mitochondria, increasing the formation of lipid peroxides and ferroptosis programmed cell death. Serum lipid peroxides and acute phase proteins are elevated, and regulatory T lymphocytes (Tregs) are dysfunctional, impairing immune-mediated neuroprotection. Macrophages are pro-inflammatory; the expression of genes involved in inflammation is increased in peripheral monocytes/macrophages of ALS patients. Suppressing these multiple components of inflammation is an important therapeutic goal and provides an opportunity to interrupt the self-propagating cytotoxic cycle. Two clinical trials with autologous infusions of ex vivo expanded Tregs have been safe and well tolerated, with promising clinical results associated with suppression of pro-inflammatory lipid peroxides.

Reduced parietal activation in participants with mild cognitive impairments during visual-spatial processing measured with functional near-infrared spectroscopy

Functional Near Infrared Spectroscopy (fNIRS) may be a suitable, simple, and cost-effective brain imaging technique for detecting divergent neuronal patterns at an early stage of neurodegeneration. In course of Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD), a deficit in visual-spatial processing, located in the parietal cortex, is a reliable risk factor. Earlier, we established the application of the clock-hand-angle-discrimination task (ADT) during fNIRS to identify neuronal correlates of the visual-spatial processing in a healthy elderly sample. In this analysis, we aimed to measure and find out differences in the hemodynamic response in MCI participants compared to matched healthy controls. As expected, MCI participants showed more errors over all conditions of pointer length and a higher reaction time in the long and middle pointer length condition. Moreover, results revealed a significant reduction of cortical activation in MCI patients. There was a generally increased activity in both the right as compared to the left hemisphere and the superior parietal brain region as compared to the inferior parietal brain region in both groups. In summary, fNIRS can be implemented in the measurement of visual-spatial processing in MCI patients and healthy elderly based on ADT. MCI participants had difficulties to cope with the ADT. Since neuronal hypoactivity occurs with concomitant behavioral deficits, an additional analysis was performed on a subgroup of MCI patients who performed as well as the control group in behavior. This subgroup analysis also showed a hypoactivation of the parietal cortex, without evidence of a compensatory activation. Therefore, we assume that MCI patients are characterized by a deficit in the parietal cortex. Overall, these findings confirm our hypothesis that hemodynamic deficits in visual-spatial processing, localized in the parietal cortex, are reliable and early diagnostic markers for cognitive decline in risk groups for the development of AD.

Salivaomics as a Potential Tool for Predicting Alzheimer's Disease During the Early Stages of Neurodegeneration.

Background:The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood and the relationships between systemic abnormalities in metabolism and AD/AMCI pathogenesis are unclear.Objective:The aim of the study was to compare the metabolomic and proteomic signature of saliva from cognitively normal and patients diagnosed with MCI or AD, to identify specific cellular pathways altered with the progression of the disease.Methods:We analyzed 80 saliva samples from individuals with MCI or AD as well as age- and gender-matched healthy controls. Saliva proteomic and metabolomic analyses were conducted utilizing mass spectrometry methods and data combined using pathway analysis.Results:We found significant alterations in multiple cellular pathways, demonstrating that at the omics level, disease progression impacts numerous cellular processes. Multivariate statistics using SIMCA showed that partial least squares-data analysis could be used to provide separation of the three groups.Conclusion:This study found significant changes in metabolites and proteins from multiple cellular pathways in saliva. These changes were associated with AD, demonstrating that this approach might prove useful to identify new biomarkers based upon integration of multi-omics parameters.

Multi-scale modeling for systematically understanding the key roles of microglia in AD development

Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States. Unfortunately, current therapies are largely palliative and several potential drug candidates have failed in late-stage clinical trials. Studies suggest that microglia-mediated neuroinflammation might be responsible for the failures of various therapies. Microglia contribute to Aβ clearance in the early stage of neurodegeneration and may contribute to AD development at the late stage by releasing pro-inflammatory cytokines. However, the activation profile and phenotypic changes of microglia during the development of AD are poorly understood. To systematically understand the key role of microglia in AD progression and predict the optimal therapeutic strategy in silico, we developed a 3D multi-scale model of AD (MSMAD) by integrating multi-level experimental data, to manipulate the neurodegeneration in a simulated system. Based on our analysis, we revealed that how TREM2-related signal transduction leads to an imbalance in the activation of different microglia phenotypes, thereby promoting AD development. Our MSMAD model also provides an optimal therapeutic strategy for improving the outcome of AD treatment.

The antibiotic doxycycline mimics the NGF signaling in PC12 cells: A relevant mechanism for neuroprotection

Doxycycline has been used as antibiotic since the 1960s. Recently, studies have shown that doxycycline is neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to anti-inflammatory and anti-apoptotic effects. However, it is not known if doxycycline has neurotrophic potential, which is relevant, considering the role of axonal degeneration at the early stages of neurodegeneration in Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease as well as in normal aging. Axons are preceded by the formation of neurites, the hallmark of the neuronal differentiation induced by neurotrophins like NGF. Therefore, the modulation of neurotrophin receptors aimed at formation and regeneration of axons has been proposed as a strategy to delay the progression of neurodegeneration and has gained relevance as new techniques for early diagnosis arise. Based on these premises, we investigated the potential of doxycycline to mimic the effects of Nerve Growth Factor (NGF) with focus on the signaling pathways and neuronal modulators of neurite initiation, growth and branching. We used PC12 cells, a neuronal model widely employed to study the neurotrophic pathways and mechanisms induced by NGF. Results showed that doxycycline induced neurite outgrowth via activation of the trkA receptor and the downstream signaling pathways, PI3K/Akt and MAPK/ERK, without inducing the expression of NGF. Doxycycline also increased the expression of GAP-43, synapsin I and NF200, proteins involved in axonal and synaptic plasticity. Altogether, these data demonstrate, for the first time, the neurotrophic potential of doxycycline, which might be useful to restore the neuronal connectivity lost at the initial phase of neurodegeneration.

Critical Molecular and Cellular Contributors to Tau Pathology.

Tauopathies represent a group of neurodegenerative diseases including Alzheimer’s disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic ‘tau seeds’ from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cells or adjacent glial cells via receptor-mediated endocytosis facilitate disease spread through the brain. While neuroprotective effects of glial cells—including phagocytotic microglial and astroglial phenotypes—have been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (MAPT) gene mutations and the strongest genetic risk factor of tauopathies—an increase in the presence of the ε2 allele of apolipoprotein E (ApoE)—provide important clues to understanding tau pathology progression. In this review, we describe the crucial signaling pathways and diverse cellular contributors to the progression of tauopathies. A systematic understanding of disease pathogenesis provides novel insights into therapeutic targets within altered signaling pathways and is of great significance for discovering effective treatments for tauopathies.

Role of VDAC Isoforms in Alpha-Synuclein Entry into Mitochondria

Parkinson's disease (PD) patients show loss of neurons, mitochondrial dysfunction, and the presence of Lewy bodies. Lewy bodies are composed of misfolded α-synuclein, which is a risk factor in both familial and sporadic PD. Studies have shown that α-synuclein can cause mitochondrial dysfunction and increase reactive oxygen species production. This has been attributed to the interaction of α-synuclein with complexes of the electron transport chain in the inner mitochondrial membrane, but it is not clear how α-synuclein crosses the outer membrane to enter the mitochondria. In neurons, α-synuclein has been shown to bind Voltage-Dependent Anion Channel (VDAC), an outer mitochondrial membrane protein that shuttles metabolites between the cytosol and the mitochondria. Also, single-channel electrophysiology experiments show that monomeric α-synuclein can transiently block and translocate through all VDAC isoforms. However, the three VDAC isoforms in mammals — VDAC1, VDAC2, and VDAC3 that form channels of almost identical conductance and anion selectivity —show distinctly different interaction with α-synuclein in experiments with reconstituted VDACs. To understand the mechanism of α-synuclein translocation into mitochondria in live cells, we performed Förster Resonance Energy Transfer (FRET) microscopy using Alexa488-α-synuclein and VDAC1, 2 or 3 -GFP. The change in FRET signal as α-synuclein enters VDAC pore and translocates through it was used to visualize α-synuclein entry into the mitochondria. The contribution of each isoform in α-synuclein translocation was studied by knocking down individual VDAC isoforms in live cells. Elucidating the mechanism of α-synuclein entry into mitochondria and, in particular, the role of each VDAC isoform in α-synuclein translocation is crucial for understanding of the impact of α-synuclein in mitochondrial dysfunction and the ways to ameliorate mitochondrial function at the early stages of neurodegeneration.

Retinal ganglion cell degeneration correlates with hippocampal spine loss in experimental Alzheimer\u2019s disease

Neuronal dendritic and synaptic pruning are early features of neurodegenerative diseases, including Alzheimer’s disease. In addition to brain pathology, amyloid plaque deposition, microglial activation, and cell loss occur in the retinas of human patients and animal models of Alzheimer’s disease. Retinal ganglion cells, the output neurons of the retina, are vulnerable to damage in neurodegenerative diseases and are a potential opportunity for non-invasive clinical diagnosis and monitoring of Alzheimer’s progression. However, the extent of retinal involvement in Alzheimer’s models and how well this reflects brain pathology is unclear. Here we have quantified changes in retinal ganglion cells dendritic structure and hippocampal dendritic spines in three well-studied Alzheimer’s mouse models, Tg2576, 3xTg-AD and APPNL-G-F. Dendritic complexity of DiOlistically labelled retinal ganglion cells from retinal explants was reduced in all three models in an age-, gender-, and receptive field-dependent manner. DiOlistically labelled hippocampal slices showed spine loss in CA1 apical dendrites in all three Alzheimer’s models, mirroring the early stages of neurodegeneration as seen in the retina. Morphological classification showed that loss of thin spines predominated in all. The demonstration that retinal ganglion cells dendritic field reduction occurs in parallel with hippocampal dendritic spine loss in all three Alzheimer’s models provide compelling support for the use of retinal neurodegeneration. As retinal dendritic changes are within the optical range of current clinical imaging systems (for example optical coherence tomography), our study makes a case for imaging the retina as a non-invasive way to diagnose disease and monitor progression in Alzheimer’s disease.

Scalable and robust latent trajectory class analysis using artificial likelihood.

Latent trajectory class analysis is a powerful technique to elucidate the structure underlying population heterogeneity. The standard approach relies on fully parametric modeling and is computationally impractical when the data include a large collection of non-Gaussian longitudinal features. We introduce a new approach, the first based on artificial likelihood concepts, that avoids undue modeling assumptions and is computationally tractable. We show that this new method provides reliable estimates of the underlying population structure and is from 20 to 200 times faster than conventional methods when the longitudinal features are non-Gaussian. We apply the approach to explore subgroups among research participants in the early stages ofneurodegeneration.

ClinicoPathological Correlation (CPC) ImmunoTechnologies for Monitoring Lymphotoxin Alpha

Abstract Neuroinflammation has been proposed as a target for neuroprotection. Therefore significant opportunities for preventing neurologic decline exist. ClinicoPathological Correlation (CPC) ImmunoTechnologies are critically needed for clinical utility for acute and chronic immunological and inflammatory disorders (including autoimmune neurological disorders such as Parkinson’s disease and Alzheimer’s disease) to determine if an individual has variants associated with a higher risk of disease (Gain of Function [GoF] variants); and elevated levels of analytes (circulating biomarkers). We hypothesize the neurovascular compartment plays a critical role in neurodegeneration. Using a multipronged approach, we identified specific immune cell subsets and inflammatory factors in the blood, which can potentially play a critical role in the early stages of neurodegeneration by disrupting homeostatic regulation, destabilizing the neurovascular compartment; and elevated levels of analytes (proteomic multiplexed quantification) in the cerebrospinal fluid (CSF) and plasma, which can potentially serve as robust, indicative biomarkers consistent with model of neuroinflammation contributing to neurovascular dysfunction, potentially leading to neurodegeneration. More specifically, we identified analytes (lymphotoxin/TNF-beta/LTA) in the plasma (low levels in CSF); TNF-alpha levels were low in plasma and CSF. Next-generation sequencing enabled the identification of risk variants, pathogen/virus profiles and LTA GoF variant strongly associated with increased protein production. We included distinct LTA inflammatory/autoimmune disease controls (rheumatoid arthritis, multiple sclerosis, uveitis or vasculitis).