Tangles, Toxicity, and Tau Secretion in AD – New Approaches to a Vexing Problem

Abstract

When the microtubule (MT)-associated protein tau is not bound to axonal MTs, it becomes hyperphosphorylated and vulnerable to proteolytic cleavage and other changes typically seen in the hallmark tau deposits (neurofibrillary tangles) of tau-associated neurodegenerative diseases (tauopathies). Neurofibrillary tangle formation is preceded by tau oligomerization and accompanied by covalent crosslinking and cytotoxicity, making tangle cytopathogenesis a natural central focus of studies directed at understanding the role of tau in neurodegenerative disease. Recent studies suggest that the formation of tau oligomers may be more closely related to tau neurotoxicity than the presence of the tangles themselves. It has also become increasingly clear that tau pathobiology involves a wide variety of other cellular abnormalities including a disruption of autophagy, vesicle trafficking mechanisms, axoplasmic transport, neuronal polarity, and even the secretion of tau, which is normally a cytosolic protein, to the extracellular space. In this review, we discuss tau misprocessing, toxicity and secretion in the context of normal tau functions in developing and mature neurons. We also compare tau cytopathology to that of other aggregation-prone proteins involved in neurodegeneration (alpha synuclein, prion protein, and APP). Finally, we consider potential mechanisms of intra- and interneuronal tau lesion spreading, an area of particular recent interest.

FRMD4A–cytohesin signaling modulates the cellular release of tau

“…Our current results clearly show that FRMD4A levels in cells are connected to the level of tau secretion. In non-neuronal cells, decreased FRMD4A levels reduce the ability of cells to secrete tau, which might lead to intracellular accumulation, hyperphosphorylation and toxicity of tau (Gendreau and Hall, 2013;Hall and Saman, 2012). However, in a more physiological and disease-relevant context, in mature cortical neurons, reduced FRMD4A levels and cytohesin inhibition, strongly promoted the secretion of endogenous tau.…”

CSF biomarkers in neurodegenerative and vascular dementias

“…It is known that misfolded Ab oligomers act as seeds inducing other Ab peptides to undergo oligomerization and aggregation in a prionlike manner (Jucker and Walker, 2011;Prado and Baron, 2012;Rosen et al, 2012). Both misfolded Ab and tau, especially aggregation intermediates, are toxic to neurons (Gendreau and Hall, 2013;Ono and Yamada, 2011). In most cases, AD is sporadic (sAD), but in about 5% of cases AD is familial and usually linked to mutations in APP, PSEN1 and PSEN2, which encode enzymes that participate in the cleavage of APP to produce b-amyloid.…”

Tau Monoclonal Antibody Generation Based on Humanized Yeast Models

“…It is therefore tempting to speculate that C-terminal phosphorylation of Tau and the establishment of the MC1/Alz50 epitope define the transition between Tau low order and higher order oligomeric structures. Another important aspect is disease propagation by the secretion and uptake of Tau oligomers that act as seeding templates for Tau misfolding and toxicity (63). In this context, we recently developed a lentivirus-mediated rat model that allowed us to monitor the spreading of Tau pathology from the CA1 region of the hippocampus to other brain areas, including the most distant ones (64,65).…”