Untangling the Tauopathy for Alzheimer’s disease and parkinsonism

Abstract

Tau is a microtubule-associated protein that mainly localizes to the axon to stabilize axonal microtubule structure and neuronal connectivity. Tau pathology is one of the most common proteinopathies that associates with age-dependent neurodegenerative diseases including Alzheimer’s disease (AD), and various Parkinsonism. Tau protein undergoes a plethora of intra-molecular modifications and some altered forms promote the production of toxic oligomeric tau and paired helical filaments, and through which further assemble into neurofibrillary tangles, also known as tauopathy. In this review, we will discuss the recent advances of the tauopathy research, primarily focusing on its association with the early axonal manifestation of axonal transport defect, axonal mitochondrial stress, autophagic vesicle accumulation and the proceeding of axon destruction, and the pathogenic Tau spreading across the synapse. Two alternative strategies either by targeting tau protein itself or by improving the age-related physiological decline are currently racing to find the hopeful treatment for tauopathy. Undoubtedly, more studies are needed to combat this devastating condition that has already affected millions of people in our aging population.

Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases

“…The microtubule-associated protein Tau is a major pathogenic protein in patients with AD, Parkinsonism and other types of dementia and neurological disorders. Tau proteins are intrinsically unstructured and they interact with each other to form high-ordered structures in different disease conditions, including neurofibrillary tangles (NFTs), which represent the major pathological hallmark of AD [ 81 ]. The development of the NFT burden has been well-characterized regarding its accumulation in different regions of the brain [ 82 , 83 ].…”

“…On the molecular level, pathogenic Tau can place stress on the neuron in multiple ways [ 81 ]. Normally, Tau is associated with microtubules by which its structure is supported.…”

Insights into Disease-Associated Tau Impact on Mitochondria

“…Finally, PHFs further self-assemble to form more organized aggregates, and eventually develop insoluble NFTs inside neurons. The following sequestration of NFTs together with compromised cytoskeleton dynamics impairs normal axonal transport, and hence contributes to synaptic dysfunction and neurodegeneration [ 74 , 75 ]. In addition, alterations of tau itself, such as mutations in the MAPT gene, can also contribute to tau aggregation.…”

Retromer in Synaptic Function and Pathology

“…Hyperphosphorylated and misfolded Tau oligomers accumulate at pre- and postsynaptic sites at early disease stages (Spires-Jones and Hyman, 2014 ; Tai et al, 2014 ), and different Tau forms can disrupt pre- and postsynaptic functions (Hoover et al, 2010 ; Ittner et al, 2010 ; Zhou et al, 2017 ; McInnes et al, 2018 ). The prion-like spread of Tau pathology between brain regions (Braak and Braak, 1991 ) appears to occur via synapses, and seed-competent Tau aggregates have been found enriched in synaptosomes (Chang et al, 2018 ; DeVos et al, 2018 ). Taken together, these observations point at synaptic retromer systems as possible players in early AD pathogenesis.…”