Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration

Abstract

Missorting of Tau from axons to the somatodendritic compartment of neurons is a hallmark of Alzheimer's disease, but the mechanisms underlying normal sorting and pathological failure are poorly understood. Here, we used several Tau constructs labelled with photoconvertible Dendra2 to analyse its mobility in polarized neurons. This revealed a novel mechanism of sorting-a retrograde barrier in the axon initial segment (AIS) operating as cellular rectifier. It allows anterograde flow of axonal Tau but prevents retrograde flow back into soma and dendrites. The barrier requires binding of Tau to microtubules but does not require F-actin and thus is distinct from the sorting of membrane-associated proteins at the AIS. The barrier breaks down when Tau is phosphorylated in its repeat domain and detached from microtubules, for example, by the kinase MARK/Par1. These observations link the pathological hallmarks of Tau missorting and hyperphosphorylation in neurodegenerative diseases.

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

“…5a,b). As acetylation of tau has been shown to correlate with decreased MT-binding capability 16 , which induces disruption of tau retrograde barrier 15 , we analysed tau localization on exposure to Ab. In 3 DIV neurons treated with 100 nM Ab, tau-1 staining was present also in minor neurites (Fig.…”

“…In the maintenance of tau retrograde barrier, not only tau binding to MT is fundamental but also MT stability per se in the region overlapping with AIS 15 where EB3 is found enriched and less mobile 21 . To understand the possible mechanism of action of Ab on axonal polarity in view of the observed missorting of tau-1, we measured the rate of movement of EB3 in the AIS (Fig.…”

“…However, the mechanisms and the targets through which Ab affects cytoskeletal dynamics, and how these may influence axonal elongation or retraction, tau localization and neuronal polarity are still unclear. We exposed neurons both to soluble Ab peptide that is responsible for Ab-induced toxicity 13 and for the severity of AD 14 , to study MT dynamics, which are crucial in maintaining the integrity of AIS and the axonal localization of tau 15 ; and to beads coated with Ab to study the direct local effect of extracellular Ab on actin remodelling, which regulate growth cone movements and axon growth.…”

Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

“…Progression of NFT pathology is closely correlated with both increased neurodegeneration and cognitive decline in AD (3) and other tauopathies, such as frontotemporal dementia (4,5). The assumption that mislocalization of tau into the somatodendritic compartment (6) and accumulation of fibrillar aggregates in NFTs mediates neurodegeneration underlies most current therapeutic strategies aimed at preventing NFT formation or disrupting existing NFTs (7,8). Although several disease-associated mutations cause both aggregation of tau and neurodegeneration, whether NFTs per se contribute to neuronal and network dysfunction in vivo is unknown (9).…”

Hyperphosphorylation of Tau Protein in Down ’s Dementia and Alzheimer’s Disease: Methylation and Implications in Prevention and Therapy

“…The authors propose that calcium channel blocking as a therapeutic strategy using isradipine which is a FDA approved dihyropyridine that selectively binds to Ca (v) 1.2 in the hippocampus and in their studies in vitro lessened the toxicity of beta amyloid. They discovered that intraneuronal or soluble extracellular Aβ can induce protein kinase A (PKA), which in turn binds to LTCC and promotes increased Ca2+ influx leading to hyperphosphorylation of tau and suppression of autophagy which is a cleaning system within the cell [27].…”