Potential Mechanisms of Tunneling Nanotube Formation and Their Role in Pathology Spread in Alzheimer's Disease and Other Proteinopathies

Abstract

Alzheimer's disease (AD) is the most common type of dementia worldwide. The etiopathogenesis of this disease remains unknown. Currently, several hypotheses attempt to explain its cause, with the most well-studied being the cholinergic, beta-amyloid (Aβ), and Tau hypotheses. Lately, there has been increasing interest in the role of immunological factors and other proteins such as alpha-synuclein (α-syn) and transactive response DNA-binding protein of 43 kDa (TDP-43). Recent studies emphasize the role of tunneling nanotubes (TNTs) in the spread of pathological proteins within the brains of AD patients. TNTs are small membrane protrusions composed of F-actin that connect non-adjacent cells. Conditions such as pathogen infections, oxidative stress, inflammation, and misfolded protein accumulation lead to the formation of TNTs. These structures have been shown to transport pathological proteins such as Aβ, Tau, α-syn, and TDP-43 between central nervous system (CNS) cells, as confirmed by in vitro studies. Besides their role in spreading pathology, TNTs may also have protective functions. Neurons burdened with α-syn can transfer protein aggregates to glial cells and receive healthy mitochondria, thereby reducing cellular stress associated with α-syn accumulation. Current AD treatments focus on alleviating symptoms, and clinical trials with Aβ-lowering drugs have proven ineffective. Therefore, intensifying research on TNTs could bring scientists closer to a better understanding of AD and the development of effective therapies.

Keywords: Alzheimer’s disease; TDP-43; Tau proteins; alpha-synuclein; beta-amyloid; dementia; etiopathogenesis; tunneling nanotubes.

Figure 1

Tunneling nanotubes (TNTs) are tubular, membranous structures that contain F-actin. These structures often consist of bundles of individuals (iTNTs), where each iTNT is encased by a plasma membrane and interconnected with others through bridging threads containing N-cadherin. TNTs are classified into two categories based on their diameter: “thin” TNTs and “thick” TNTs. “Thin” TNTs, ranging from 20 to 700 nanometers in diameter, primarily facilitate the exchange of smaller cargo, such as secondary messengers, small peptides, and molecules with a molecular weight below 1.2 kDa. Conversely, “thick” TNTs, which exceed 700 nanometers in diameter, are capable of transporting larger cargo, including organelles, viruses, and molecules larger than 1.2 kDa.

Figure 2

Evidence indicates that amyloid beta (Aβ) can move bidirectionally through tunneling nanotubes (TNTs) in various cell lines. In Alzheimer’s disease (AD), excess Aβ released from cells is rapidly transferred to neighboring cells via TNTs, which accelerates disease progression. Tau may also trigger TNT formation, and fibrillar Tau transport through TNTs has been confirmed in vitro. Both exogenous and endogenous Tau aggregates can be transmitted between cells and have been detected inside TNTs in neuronal cell lines. Alpha-synuclein (α-syn) may be transferred via TNTs in vitro, reducing its burden in donor cells. Similar to Tau, α-syn increases the number of TNT connections compared to untreated cells and can be transported between neurons and microglia. α-Syn aggregates are preferentially transferred from neuronal to microglial cells, while mitochondria are transported in the opposite direction. Additionally, in lymphoblasts from AD patients, increased formation of actin protrusions resembling TNTs or TNT-like structures was observed. Transactive response DNA-binding protein of 43 kDa (TDP-43) aggregates were found alongside F-actin fibers in the cytosolic compartment of these cells and were also detected within tubular actin channels.