Accumulation Of Neurofibrillary Tangles Research Articles

Ascorbic acid modulates prefrontal cortex cellular changes in androgen deprived rats

Background: Testosterone deficiency has been implicated in numerous neurodegenerative diseases such as Alzheimer's, Parkinson and Huntington's disease. We used a model of androgen deprived rats to determine the effects of ascorbic acid on prefrontal cortex (PFC) cellular changes associated with a subset population of androgen deprived patients.Methodology: Chemical castration (using testosterone antagonist) as well as orchiectomy can induce androgen deprivation. Twenty-one (21) adult male Wistar rats with an average weight of 170g±10g were randomly assigned into three groups with each group containing seven (7) rats. Group A was control group, Group B= Orchiectomy + Flutamide (11 mg/kg body weight), and group C= Orchiectomy + Flutamide (11 mg/kg body weight)+Ascorbic acid (100 mg/kg body weight). Treatment lasted for 30 days. Nitric oxide and Malondialdehyde levels were assessed; while serum testosterone level was assayed. Histological, Histochemical, and immunohistochemical investigations were performed using Hematoxylin & Eosin, Cresyl fast violet, and Bielschowsky stains respectively.Result: Our results showed increased expression of Nitric Oxide (NO), and increased lipid peroxidation (MDA) in the PFC of orchiectomized animals with altered cytoarchitectural morphology evidenced by decreased Nissl staining polarity in neuronal axons and aggregation of neurofibrillary tangles. Oxidative and nitrosative stress were well modulated in animals treated with ascorbic acid with unaltered prefrontal cortex morphology.Conclusion: The results indicated that decline in brain androgen activities caused nitrosative and oxidative stress-driven pathology in the prefrontal cortex while supplementing endogenous ascorbic acid offered therapeutic value by scavenging free radicals in the prefrontal cortex

MicroPET Imaging Assessment of Brain Tau and Amyloid Deposition in 6 × Tg Alzheimer's Disease Model Mice.

Alzheimer’s disease (AD) is characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of neurofibrillary tangles (NFT). Amyloid beta (Aβ) and tau imaging are widely used for diagnosing and monitoring AD in clinical settings. We evaluated the pathology of a recently developed 6 × Tg − AD (6 × Tg) mouse model by crossbreeding 5 × FAD mice with mice expressing mutant (P301L) tau protein using micro-positron emission tomography (PET) image analysis. PET studies were performed in these 6 × Tg mice using [18F]Flutemetamol, which is an amyloid PET radiotracer; [18F]THK5351 and [18F]MK6240, which are tau PET radiotracers; moreover, [18F]DPA714, which is a translocator protein (TSPO) radiotracer, and comparisons were made with age-matched mice of their respective parental strains. We compared group differences in standardized uptake value ratio (SUVR), kinetic parameters, biodistribution, and histopathology. [18F]Flutemetamol images showed prominent cortical uptake and matched well with 6E10 staining images from 2-month-old 6 × Tg mice. [18F]Flutemetamol images showed a significant correlation with [18F]DPA714 in the cortex and hippocampus. [18F]THK5351 images revealed prominent hippocampal uptake and matched well with AT8 immunostaining images in 4-month-old 6 × Tg mice. Moreover, [18F]THK5351 images were confirmed using [18F]MK6240, which revealed significant correlations in the cortex and hippocampus. Uptake of [18F]THK5351 or [18F]MK6240 was highly correlated with [18F]Flutemetamol in 4-month-old 6 × Tg mice. In conclusion, PET imaging revealed significant age-related uptake of Aβ, tau, and TSPO in 6 × Tg mice, which was highly correlated with age-dependent pathology.

Blood-Based Biomarkers for Alzheimer's Disease Diagnosis and Progression: An Overview.

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1–42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease.

Implication of Adult Hippocampal Neurogenesis in Alzheimer's Disease and Potential Therapeutic Approaches.

Alzheimer’s disease is the most common neurodegenerative disease, affecting more than 6 million US citizens and representing the most prevalent cause for dementia. Neurogenesis has been repeatedly reported to be impaired in AD mouse models, but the reason for this impairment remains unclear. Several key factors play a crucial role in AD including Aβ accumulation, intracellular neurofibrillary tangles accumulation, and neuronal loss (specifically in the dentate gyrus of the hippocampus). Neurofibrillary tangles have been long associated with the neuronal loss in the dentate gyrus. Of note, Aβ accumulation plays an important role in the impairment of neurogenesis, but recent studies started to shed a light on the role of APP gene expression on the neurogenesis process. In this review, we will discuss the recent approaches to neurogenesis in Alzheimer disease and update the development of therapeutic methods.

Endocannabinoid metabolism and Alzheimer's disease.

Endocannabinoid metabolism and Alzheimer's disease.

Extracranial carotid atherosclerosis is associated with increased neurofibrillary tangle accumulation.

We sought to determine whether extracranial carotid atherosclerotic disease (ECAD) is associated with increased key neurodegenerative pathology such as neurofibrillary tangle (NFT), beta-amyloid plaque, or cerebral amyloid angiopathy (CAA) accumulation, findings associated with Alzheimer's disease (AD) and other dementias. Our prospective, longitudinal, clinicopathologic study, the AZSAND (Arizona study of aging and neurodegenerative disorders) and Brain and Body Donation Program, recorded the presence or absence of clinically diagnosed ECAD and performed semiquantitative density estimates of NFT, beta-amyloid plaque, and CAA at death. After adjusting for potential confounding factors determined by logistic regression analysis, histopathology density scores were evaluated in individuals with ECAD (n= 66) and those without ECAD (n= 125). We found that the presence of ECAD was associated with a 21% greater NFT burden at death compared with no ECAD (P= .02). Anatomically, an increased NFT burden was seen throughout the brain regions evaluated but was significant in the temporal lobe (P< .05) and entorhinal cortex (P= .02). In addition, we found that subjects who had undergone carotid endarterectomy (CEA), the surgical treatment of ECAD (n= 32), had decreased NFT densities compared with those with ECAD who had not undergone CEA (n= 66; P= .04). In contrast to NFT, ECAD was not associated with beta-amyloid plaques or CAA density. These findings indicate that ECAD is associated with the NFT burden in the temporal lobe and entorhinal cortex, which has clinical significance for AD and non-AD dementias and cognitive dysfunction. Further understanding of whether ECAD increases the risk of neurodegenerative brain changes is highly relevant because ECAD is a treatable disease that has not, otherwise, been evaluated for nor specifically treated as a dementia risk factor.

The tangled story of carotid disease, carotid revascularization, and Alzheimer's disease: The plot thickens.

Arias et al1 present an autopsy study showing that increased neurofibrillary tangle accumulation as commonly seen in Alzheimer's disease was associated with the diagnosis of carotid artery stenosis. Similar to other studies, they did not see increased β-amyloid plaque in patients with carotid disease.2,3 Tantalizingly, they further show that patients who underwent carotid endarterectomy for their carotid disease had significantly lower neurofibrillary densities compared with those who did not undergo carotid intervention.

In vivo analysis of synaptic degeneration with Aβ plaque and NFT accumulation in cognitive decline

AbstractBackground[11C]UCB‐J selectively binds to synaptic vesicle glycoprotein 2A (SV2A) and may be used to measure synaptic density in synaptopathies. Along with the accumulation of amyloid‐b plaques and neurofibrillary tau tangles, neurodegeneration is a hallmark of Alzheimer’s disease (AD) dementia. Synaptic density may be decreased due to AD pathology, resulting in cognitive dysfunction. We examined whether synaptic density was related to the accumulation of protein aggregates characteristic of AD as well as cognitive function.MethodThirty subjects (68.6±6.2 years old, 20F/10M) recruited from the Wisconsin ADRC and the Wisconsin Registry for Alzheimer’s Prevention study underwent [11C]UCB‐J dynamic PET imaging to assess synaptic density, T1w‐MR imaging, and the Rey Auditory Verbal Learning Test (RAVLT). Twenty‐four participants also completed [11C]PiB dynamic imaging to assess amyloid‐b plaque accumulation and [18F]MK‐6240 dynamic imaging to assess neurofibrillary tangle accumulation. T1w‐MRI was used to derive subject‐specific regions of interest (ROIs) as well as to calculate the matrices required to transform images into MNI152 space. Global amyloid burden was ascertained by taking the mean PiB DVR across eight bilateral AAL‐based ROIs. Neurofibrillary tau tangle accumulation in the entorhinal cortex was quantified using the [18F]MK‐6240 SUV ratio. Subject‐specific hippocampus ROIs for [11C]UCB‐J analysis were defined using FreeSurfer (v7) segmentation of the participant’s MR image.ResultUsing data from the n=24 subjects, [11C]UCB‐J binding in the hippocampus was significantly associated with [11C]PiB global DVR (R2 = 0.24, P = 0.01) and [18F]MK‐6240 uptake in the entorhinal cortex (R2 = 0.17, P = 0.04). After correcting for hippocampus volume size, significance decreased for both measures (R2 = 0.28, P = 0.05 for [11C]PiB global DVR; R2 = 0.17, P = 0.05 for [18F]MK‐6240 entorhinal cortex SUVR). [11C]UCB‐J binding in the hippocampus was not significantly related to RAVLT immediate recall (R2 = 0.52, P = 0.08) but was significantly associated with RAVLT delayed recall (R2 = 0.55, P = 0.04).ConclusionFindings suggest that synaptic impairment is related to amyloid‐b and neurofibrillary tau tangle accumulation as well as worse performance on RAVLT delayed recall. Future work will test the longitudinal relationship between accumulation of AD pathology, synapse loss, and cognitive decline.

Could G6PD overexpression play a role in the prevention of Alzheimer's disease?

Alzheimer's Disease (AD) is a neurodegenerative disorder and the most common type of dementia in the elderly. AD is characterized by the beta-amyloid (Aβ) peptide and neurofibrillary tangles accumulation in the brain, accompanied by a progressive neuronal dysfunction and neurodegeneration. Along with these phenomena, it should be noticed that alterations in energy metabolism and an increased production of free radicals leading to an increased in the oxidative stress, are also characteristics of AD. Against these reactive oxygen species (ROS), the cellular antioxidant defences use NADPH as reducing agent, mainly produced by glucose-6-phosphate dehydrogenase (G6PD) enzyme. The proposal of this study was to look into if G6PD overexpression had any effect on the onset of AD. To this end, we used three mouse cohorts: wild-type (WT) mice, double APPswe/PSEN1dE9 transgenic (2xTg) mice and a new triple APPswe/PSEN1dE9/G6PD transgenic (3xTg) mice that we generated by crossing between simple G6PD transgenic mice and the AD-like pathology model (2xTg mice). We compared the three groups at a functional, cognitive, biochemical and metabolic level. We compare a 3xTg mouse cohort (n=12 males, 14 females) with a WT mouse cohort (n=9 males, 13 females) and a 2xTg mouse cohort (n= 13 males, 11 females). We evaluated different functional parameters (grip strength, motor coordination and endurance) through grip strength test, rotarod test and incremental-speed test on a treadmill; cognitive parameters (implicit memory, learning) through passive avoidance test and Hebb Williams mazes; biochemical measurements (G6PD activity, oxidative stress markers such as malondialdehyde, protein carbonylation); and metabolic changes through indirect calorimetry. All tests were performed in 12-14-month-old mice. 3xTg female mice showed a better functional performance than WT and 2xTg females, while male mice showed no significant differences between the three groups of mice. The 3xTg mouse cohort also exhibited significant improvements in cognitive skills over 2xTg and WT groups. Preliminary results show a significantly higher respiratory quotient (RQ) in 3xTg females compared to 2xTg females. At the biochemical level, we did not find differences in the oxidative state between the 3 genotypes. G6PD overexpression could play a role in the onset delay of Alzheimer's disease in murine models.

Profiling tau accumulation with SPReAD: Sub-stages for propagation regions in Alzheimer's disease.

Monitoring pathophysiological stages of Alzheimer's Disease (AD) is important for understanding, forecasting and ultimately treating the disease. One prominent example of such staging is the spread of tau protein manifested in the stage-wise accumulation of neurofibrillary tangles [1]. With the development of high-affinity tau PET tracers, it is possible to track the protein accumulation in vivo [3]. Quantification of the spatial continuity of such spread longitudinally could help disentangle the tau propagation mechanism. We introduce "Sub-stages for Propagation Regions in Alzheimer's Disease" ("SPReAD") as a method to represent Braak stage related tau tracer uptake continuously as a spatial series. To achieve such mapping, we projected tau uptake data to surfaces [2] with discrete Braak stage parcels (Fig. 1, top left), and, by assigning vertex weights recursively according to the neighbourhood relationships of adjacent stages' regions, we made a sub-stage map (Fig. 1, bottom left); then, we sampled average uptake values within these sub-stages to obtain each subject's uptake profile. We validated SPReAD using [18F]MK6240 standardized uptake value ratio (SUVR) data from 20 AD subjects at 2 visits; 5 AD subjects at 3 visits; 2 AD subjects at 4 visits, with approximately 12-month inter-visit interval, all amyloid positive; Braak stage discordant cases were excluded. The resulting sub-stage profiles appeared highly correlated across visits for AD patients (r=0.9; p<0.01). The differences between baseline and follow-up SUVRs were generally less prominent at the early stages, with especially significantly greater SUVR (p<0.05, two-sample t-test) at the follow-up at the latest Braak stage for a given subject (Fig. 1, right shows two such subjects with Braak stage VI). The Braak sub-stage profile representation using SPReAD helps identify changes within a given Braak stage and across the stages, both in terms of magnitude and spatial progression. It reduces surface manifold data into more interpretable spatial series, at the same time providing information on subtle between-stage transitions which represents a novel systematic way to quantify tau propagation patterns.

Correlation between 18F-THK5351 tau PET imaging and the progression of neuropathology and clinical signs in a mouse model.

Several common neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (ptau). In Alzheimer's disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone. Abnormal ptau leads to the formation of insoluble aggregates in tauopathies such as AD. Positron emission tomography (PET) imaging is a promising avenue that may identify tau aggregates in vivo cross-sectionally and longitudinally in various dementia conditions. In this study, tau transgenic P301S mice, from 6 to 12 months of age, were analyzed by longitudinal in vivo PET brain imaging utilizing the tau ligand [18 F]THK5351, as well as histological, biochemical, and behavioral characterization over time. Our results demonstrate elevated in vivo [18 F]-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, and motor, memory and learning impairment. This study indicates that [18 F]-THK5351 may facilitate detection of aberrant tau aggregation and deposition in order to differentiate between tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials. This work was partially funded by Department of Defense Peer Reviewed Alzheimer's Research Program Convergence Science. Research Award grant AZ160106 and Alzheimer's Association New Investigator Research Grant NIRG-394284 to IMG.

Application of histopathologically derived 3D tau burden map as in‐vivo region of interest for biomarker analysis

AbstractBackgroundQuantitative three‐dimensional maps of tau neurofibrillary tangles (NFT) burden derived from dense serial histology have potential application for in‐vivo biomarker studies. We constructed a group‐level NFT burden map from 15 medial temporal lobe (MTL) specimens, majority with Primary Age‐Related Tauopathy (PART) or low‐level Alzheimer’s disease neuropathologic change, and showed relatively greater NFT burden in the anterior vs. posterior MTL. We investigated whether in‐vivo MRI and PET measures in ROIs derived from this map show meaningful biological relationships.MethodMultimodal in‐vivo imaging data from 292 participants in the Aging Brain Cohort were used. The group‐level NFT burden map was mapped to each participant’s MRI to define an ROI mask, further divided into anterior (aMTL) and posterior (pMTL) ROIs. Cortical thickness (N=292) and 18F‐Flortaucipir SUVR maps (N=86) were computed. Participants’ age was correlated with average thickness in the aMTL, pMTL, and anatomically defined MTL ROIs. 18F‐Flortaucipir uptake was compared between aMTL and pMTL. The analyses were repeated in subsets of cognitive normal participants, and those with negative amyloid PET scans.ResultCortical thickness in the aMTL ROI showed stronger correlation with age than pMTL and anatomically defined MTL subregional thickness. A polynomial fit provided the best age regression, with older participants showing a parabolic decline in thickness around age 60, when substantial NFT accumulation begins in MTL. Further, tau tracer uptake in aMTL was slightly but significantly higher than in pMTL (SUVR 1.19 vs. 1.18, p=0.02).ConclusionWe demonstrate the potential use of ex‐vivo NFT burden maps for in‐vivo image analysis. NFT deposition is particularly prominent in the anterior MTL in cases without or with low amyloid burden and at early Braak stage. Prior work suggests that even in the absence of amyloid, this tangle pathology may drive neurodegeneration in the aging population. Here we show that cortical thickness, a biormarker for neurodegeneration, when measured within a histopathologically‐defined region enriched for PART NFTs in the aMTL, is better correlated with age than when measured within anatomically defined subregions, suggesting that the relationship may be driven by PART. Greater tau tracer uptake in the aMTL ROI further supports this notion.

Current Status and Challenges of Stem Cell Treatment for Alzheimer's Disease.

Neurodegenerative diseases called tauopathies, such as Alzheimer’s disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson’s disease, among others, are characterized by the pathological processing and accumulation of tau protein. AD is the most prevalent neurodegenerative disease and is characterized by two lesions: neurofibrillary tangles (NFTs) and neuritic plaques. The presence of NFTs in the hippocampus and neocortex in early and advanced stages, respectively, correlates with the patient’s cognitive deterioration. So far, no drugs can prevent, decrease, or limit neuronal death due to abnormal pathological tau accumulation. Among potential non-pharmacological treatments, physical exercise has been shown to stimulate the development of stem cells (SCs) and may be useful in early stages. However, this does not prevent neuronal death from the massive accumulation of NFTs. In recent years, SCs therapies have emerged as a promising tool to repopulate areas involved in cognition in neurodegenerative diseases. Unfortunately, protocols for SCs therapy are still being developed and the mechanism of action of such therapy remains unclear. In this review, we show the advances and limitations of SCs therapy. Finally, we provide a critical analysis of its clinical use for AD.

Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study.

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer’s disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer\u2019s disease

Alzheimer’s disease (AD) is characterized by amyloid (Aβ) protein aggregation and neurofibrillary tangles accumulation, accompanied by neuroinflammation. With all the therapeutic attempts targeting these biomarkers having been unsuccessful, the understanding of early mechanisms involved in the pathology is of paramount importance. Dopaminergic system involvement in AD has been suggested, particularly through the appearance of dopaminergic dysfunction-related neuropsychiatric symptoms and an overall worsening of cognitive and behavioral symptoms. In this study, we reported an early dopaminergic dysfunction in a mouse model presenting both amyloid and Tau pathology. 3xTg-AD mice showed an increase of postsynaptic D2/3R receptors density in the striatum and D2/3-autoreceptors in SN/VTA cell bodies. Functionally, a reduction of anxiety-like behavior, an increase in locomotor activity and D2R hyper-sensitivity to quinpirole stimulation have been observed. In addition, microglial cells in the striatum showed an early inflammatory response, suggesting its participation in dopaminergic alterations. These events are observed at an age when tau accumulation and Aβ deposits in the hippocampus are low. Thus, our results suggest that early dopaminergic dysfunction could have consequences in behavior and cognitive function, and may shed light on future therapeutic pathways of AD.

The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease.

Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. It is associated with the development of secondary complications resulting in several comorbidities. Recent studies have revealed an increased risk of developing cognitive dysfunction or dementia in diabetes patients. Diabetes mellitus is considered a risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is increasing evidence to support a link between DM and AD. Studies have shown the dysfunction of insulin signaling in the brain, resulting in increased tau protein phosphorylation (hyperphosphorylation), a hallmark and biomarker of AD pathology, leading to accumulation of neurofibrillary tangles. In DM, the insulin dysfunction in the brain is reported to alter the glycogen synthase kinase-3β (GSK-3β) activity showing to enhance tau phosphorylation. In DM and AD, GSK-3β signaling has been involved in the physiological and pathological processes, respectively. This potentially explains why DM patients have an increased risk of developing AD with disease progression and aging.Interestingly, several in vivo studies with oral antidiabetic drugs and insulin treatment in DM have improved cognitive function and decreased tau hyperphosphorylation. This article will review the relationship between DM and AD as it relates to tau pathology. More understanding of the link between DM and AD could change the approach researchers and clinicians take toward both diseases, potentially leading to new treatments and preventative strategies in the future.

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model.

Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD‐like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone‐lysine N‐methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5–7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.

A novel missense variant in ACAA1 contributes to early-onset Alzheimer\u2019s disease, impairs lysosomal function, and facilitates amyloid-\u03b2 pathology and cognitive decline

Alzheimer’s disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-β (Aβ) plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue, which all lead to loss of cognitive function. Pathogenic mutations in the well-known AD causal genes including APP, PSEN1, and PSEN2 impair a variety of pathways, including protein processing, axonal transport, and metabolic homeostasis. Here we identified a missense variant rs117916664 (c.896T>C, p.Asn299Ser [p.N299S]) of the acetyl-CoA acyltransferase 1 (ACAA1) gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent cohort. Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity, impairing lysosomal function, and aggravating the Aβ pathology and neuronal loss, which finally caused cognitive impairment in a murine model. Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.

Tau Protein Interaction Partners and Their Roles in Alzheimer's Disease and Other Tauopathies.

Tau protein plays a critical role in the assembly, stabilization, and modulation of microtubules, which are important for the normal function of neurons and the brain. In diseased conditions, several pathological modifications of tau protein manifest. These changes lead to tau protein aggregation and the formation of paired helical filaments (PHF) and neurofibrillary tangles (NFT), which are common hallmarks of Alzheimer’s disease and other tauopathies. The accumulation of PHFs and NFTs results in impairment of physiological functions, apoptosis, and neuronal loss, which is reflected as cognitive impairment, and in the late stages of the disease, leads to death. The causes of this pathological transformation of tau protein haven’t been fully understood yet. In both physiological and pathological conditions, tau interacts with several proteins which maintain their proper function or can participate in their pathological modifications. Interaction partners of tau protein and associated molecular pathways can either initiate and drive the tau pathology or can act neuroprotective, by reducing pathological tau proteins or inflammation. In this review, we focus on the tau as a multifunctional protein and its known interacting partners active in regulations of different processes and the roles of these proteins in Alzheimer’s disease and tauopathies.

Orientation of neurites influences severity of mechanically induced tau pathology

Chronic traumatic encephalopathy is a neurodegenerative disease associated with repeated traumatic brain injury (TBI). Chronic traumatic encephalopathy is a tauopathy, in which cognitive decline is accompanied by the accumulation of neurofibrillary tangles of the protein tau in patients’ brains. We recently found that mechanical force alone can induce tau mislocalization to dendritic spines and loss of synaptic function in in vitro neuronal cultures with random cell organization. However, in the brain, neurons are highly aligned, so here we aimed to determine how neuronal organization influences early-stage tauopathy caused by mechanical injury. Using microfabricated cell culture constructs to control the growth of neurites and an in vitro simulated TBI device to apply controlled mechanical deformation, we found that neuronal orientation with respect to the direction of a uniaxial high-strain-rate stretch injury influences the degree of tau pathology in injured neurons. We found that a mechanical stretch applied parallel to the neurite alignment induces greater mislocalization of tau proteins to dendritic spines than does a stretch with the same strain applied perpendicular to the neurites. Synaptic function, characterized by the amplitude of miniature excitatory postsynaptic currents, was similarly decreased in neurons with neurites aligned parallel to stretch, whereas in neurons aligned perpendicular to stretch, it had little to no functional loss. Experimental injury parameters (strain, strain rate, direction of stretch) were combined with a standard viscoelastic solid model to show that in our in vitro model, neurite work density during stretch correlates with tau mislocalization. These findings suggest that in a TBI, the magnitude of brain deformation is not wholly predictive of neurodegenerative consequences of TBI but that deformation relative to local neuronal architecture and the neurite mechanical energy during injury are better metrics for predicting trauma-induced tauopathy.