Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation

Abstract

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 and TSC2 genes and autosomal dominantly inherited. These mutations cause hyperactivation of the mammalian Target of Rapamycin (mTOR) pathway, leading to the development of nonmalignant masses involving various organ systems. Patients with TSC also experience neuropsychiatric symptoms collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorder (TAND). Due to research advancements in TSC, patients now live well beyond the age of 50. Many experience objective impairment of memory and executive function, supported by formal neuropsychological testing, beginning in their late 40s. Biomarker analysis has described elevated levels of phosphorylated tau-181 in the cerebrospinal fluid of patients with TAND. Tau-PET imaging has also shown focal accumulation of the radiotracer flortaucipir (AV1451), suggesting that TSC may be a neurodegenerative disorder arising from accumulation of phosphorylated tau. However, the flortaucipir tracer has been reported to have significant off-target binding, preventing definitive conclusions from being drawn about the molecular etiology of neurodegeneration in TSC. Therefore, we initiated the Colocalization of AV1451 and Phosphorylated Tau in Adult brain tissue (CAPA) study. This study aimed to determine if flortaucipir is bound to phosphorylated tau in brains of patients with TSC and further sought to determine the specific tau isoform seen in TSC. Our results show that flortaucipir labels the 3R/4R isoform of phosphorylated tau, commonly seen in Alzheimer’s disease. However, amyloid staining was negative in brains of adult patients with TSC. Therefore, we conclude that TAND symptoms are due to the accumulation of the phosphorylated tau isoform seen in Alzheimer’s disease. This study suggests that hyperactivation of the mammalian Target of Rapamycin pathway may play a role in the amyloid-independent development of 3R/4R tau aggregation. Our findings could lead to a new era of anti-tau therapies used to treat both disorders.

Robot Target Localization and Visual Navigation Based on Neural Network

“…Assuming that the principles behind neurons are found, the initial function has been taken as an important tool for counting neurons, reasoning needs to be expressed as computation, and neural networks and M-P models were planned, starting to create neural networks (ANN) [11]. Liu, in his book "Society of Behavior," reported on Hebb synapse and Hebb law education, which laid the theoretical basis for the development of neural network algorithms [12].…”

Research and Implementation of Robot Vision Scanning Tracking Algorithm Based on Deep Learning

“…Liu et al proposed a target tracking algorithm, which uses the Meanshift as the core, and the feature representation method of the two-digit histogram is selected by using the color and gray information of the target image to represent the target model. At the same time, combined with the motion detection module, the key information is provided for the path planning, navigation, and other high-level decisions of the autonomous mobile robot in the indoor environment [ 5 ]. Mayandi et al built a robot sorting experimental system based on machine vision; in this system, the targets continuously enter the operation area the system controls the robot to achieve the object sorting, the system continuously and automatically obtains the image of the object through the camera, and the software analyzes the collected images, transforms the coordinates of target objects, identifies the classification information of target objects, and maintains the movement traces of sorting targets [ 6 ].…”

Microtubule Cytoskeletal Network Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders

“…Hyperphosphorylated and aggregated into neurofibrillary tangles (NFTs), Tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies [ 48 , 90 , 102 ]. There is sufficient evidence to suggest implications of dysregulated mTOR signalling in MAP-Tau pathology observed in these neurodegenerative diseases [ 52 , 53 , 54 , 55 , 56 ]. More recent studies have shown that Tau protein pathology is also involved in several neurodevelopmental disorders, particularly those featuring hyperactivation of the mTOR pathway, including ASD [ 67 , 68 , 103 ].…”

“…Our results are consistent with the study by Caccamo et al, who showed that genetically enhanced mTOR activity facilitated Tau pathology by elevating both endogenous Tau levels and phosphorylation in the hippocampi of the TSC2 heterozygous mice [ 53 ]. Liu et al described elevated levels of phosphorylated Tau in the cerebrospinal fluid of patients with TSC, suggesting that overstimulation of the mTOR pathway may be a novel, amyloid-independent tauopathy similar to that seen in AD [ 52 ]. Moreover, studies in vitro by Tang et al have reported that up-regulated mTOR promotes Tau dyshomeostasis by mediating the synthesis, phosphorylation, and aggregation of Tau.…”

“…The destabilization of the MT system, especially anomalies in the MAP-Tau protein, has been revealed in neurodegenerative diseases, in particular in Alzheimer’s disease (AD) and other tauopathies [ 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Moreover, there is sufficient evidence to suggest the implications of defective/deregulated mTOR signalling in MAP-Tau pathology observed in these neurodegenerative disorders [ 52 , 53 , 54 , 55 , 56 , 57 , 58 ].…”