Implication of tau propagation on neurodegeneration in Alzheimer’s disease

Abstract

Propagation of tau fibrils correlate closely with neurodegeneration and memory deficits seen during the progression of Alzheimer’s disease (AD). Although it is not well-established what drives or attenuates tau spreading, new studies on human brain using positron emission tomography (PET) have shed light on how tau phosphorylation, genetic factors, and the initial epicenter of tau accumulation influence tau accumulation and propagation throughout the brain. Here, we review the latest PET studies performed across the entire AD continuum looking at the impact of amyloid load on tau pathology. We also explore the effects of structural, functional, and proximity connectivity on tau spreading in a stereotypical manner in the brain of AD patients. Since tau propagation can be quite heterogenous between individuals, we then consider how the speed and pattern of propagation are influenced by the starting localization of tau accumulation in connected brain regions. We provide an overview of some genetic variants that were shown to accelerate or slow down tau spreading. Finally, we discuss how phosphorylation of certain tau epitopes affect the spreading of tau fibrils. Since tau pathology is an early event in AD pathogenesis and is one of the best predictors of neurodegeneration and memory impairments, understanding the process by which tau spread from one brain region to another could pave the way to novel therapeutic avenues that are efficient during the early stages of the disease, before neurodegeneration induces permanent brain damage and severe memory loss.

Tau-related reduction of glucose metabolism in mild cognitive impairment occurs independently of APOE ε4 genotype and is gradually modulated by β-amyloid

“…In any case, a plausible mechanistic explanation for the uncovered tau-metabolism associations, as well as their modulation by the concurrent action of β-amyloid would necessarily involve multi-factorial, integrative scenarios of the AD progression. From a purely brain connectivity perspective, one must consider the relationship between tau deposition, abnormal structural and functional connectivity, and underlying amyloid-dependent patterns of spread [47–50]. For instance, modelling approaches by Vogel et al [51] support the notion that tau pathology propagates through neuronal connections, likely with seed origin in the medial temporal cortex, a process that is accelerated under the influence of a gradual increase in β-amyloid accumulation.…”

Clathrin mediated endocytosis in Alzheimer’s disease: cell type specific involvement in amyloid beta pathology

“…The pathogenic form of Aβ (Aβ 1-42 ) is produced when Amyloid precursor protein (APP) is endocytosed and processed in the endolysosomal pathway of neurons ( Koo and Squazzo, 1994 ; Selkoe and Hardy, 2016 ). CME has also been related to Tau pathology, primarily as a function of intercellular propagation in which aggregated pathologic Tau ( Lamontagne-Kam et al, 2023 ) is internalized via many types of endocytosis including CME ( Ando et al, 2020 ). While the potential cellular effects of Tau internalization by endocytosis are substantial ( Thal and Tome, 2022 ), the ratio of Tau internalized via CME versus other endocytic pathways is unknown and thus studies are needed to determine if CME is as prominent a mechanism of Tau internalization, as it is for Aβ uptake.…”

An Electrochemical Immunosensor with PEDOT: PSS/MWCNTs-COOH Nanocomposites as a Modified Working Electrode Material for Detecting Tau-441

“…The abnormal accumulation of Tau protein causes neurofibrillary tangles (NFTs), which lead to the degeneration of neuronal fibers and the onset of dementia in patients. Therefore, Tau protein is an important marker for the diagnosis of AD patients [10][11][12]. Because the process of obtaining CSF is complex and painful for patients, testing for AD through minimally invasive blood has been a key topic of research for scientists in recent years.…”