Report from the Tau Front: Cantoblanco 2013
Garth F Hall*
Department of Biological Sciences, University of Massachusetts Lowell, USA
- Corresponding Author:
- Garth F Hall
Department of Biological Sciences
University of Massachusetts Lowell
198 Riverside Street Lowell MA 01854, USA
Fax: 978 934 23044
E-mail: [email protected]
Received date: June 10, 2014; Accepted date: June 30, 2014; Published date: July 30, 2014
Citation: Hall GF (2014) Report from the Tau Front: Cantoblanco 2013. J Alzheimers Dis Parkinsonism 4:e133. doi:10.4172/2161-0460.1000e133
Copyright: © 2014 Hall GF, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Neuron death; Interneuronal lesion spread; Tau secretion;
Prion; Templated misfolding
PrP: Prion Protein; SNCA: Alpha Synuclein;
AD: Alzheimer’s Disease; APP: Amyloid Precursor Protein; NDD:
Neurodegenerative Disease; MAP: Microtubule Associated Protein;
MTBR: Microtubule Binding Repeat/Region
The recent interest in tau and its role in neurodegenerative
disease (NDD) has been part of a sea change in how we view protein
aggregate toxicity in NDD pathogenesis. The longstanding focus on
protein aggregate formation as a common mechanism linked to NDD
pathogenesis remains largely intact, but there has been a shift away
from large cellular and extracellular aggregates [neurofibrillary tangles
(NFTs), senile plaques (SPs), Lewy Bodies (LBs) and the like) toward
the importance of oligomers and other aggregate intermediates [1-3].
We have also seen an expansion of the hitherto largely cellular focus
on toxicity to include interneuronal aspects of the pathogenesis of
diverse NDDs, including Alzheimer’s Disease, Parkinson’s Disease, ALS
and non-AD tauopathies such as corticobasal degeneration and Pick’s
Disease. This has been accompanied by an increasing understanding
of the importance of micro RNA and mRNA-mediated mechanisms
[4-7] as well as other cellular and intercellular mechanisms and the
cytopathogenesis of multiple neurodegenerative syndromes [8-10].
This expansion of research scope at both cellular and intercellular levels
of analysis has had particularly notable effects on research into basic
and disease-associated functions of tau protein and have elucidated
the hitherto shadowy zones separating the traditional cellular focus of
tauopathy research (protein aggregate formation) from other important
disease features involving cell cycle re-entry [11-14], signal transduction
abnormalities [15,16], and the disruption of protein turnover 
localization  and secretion [19-21] mechanisms. Perhaps the
largest influence on the direction of recent NDD research has been the
idea that oligomer formation may itself be the agent of interneuronal
lesion spreading via a “prionlike” mechanism [22-26]. In the case of
tauopathy, this concept has tended to both expand and narrow the
scope of recent investigations as it focuses attention the link between
molecular [templated misfolding] and global (lesion spreading) aspects
of tauopathy at the expense of cellular considerations. All of these
developments were reflected in the focus of last year’s Cantoblanco
meeting in Madrid. While that meeting was ostensibly focused on
the title subject “Is Tau a prionlike protein?” it also brought together
current research on a variety of novel cellular and intercellular facets
of tau biology and pathobiology, which I will attempt here to frame in
a larger context.
Back to the Future – Developmental Tau Functions are
The largely neuronal  expression of tau during development
and the marked localization of tau to the axon initially drew a great deal
of attention to the developmental functions of tau and especially its role
in the development of axonal identity. Indeed, the best-characterized
and most studied function of tau outside of its regulation of MT
dynamics  before 1991 was its contribution to the generation of axonal identity in developing neurons [29,30]. Later studies revealed
important and MT-independent roles for tau in various other aspects of
axonal differentiation, including outgrowth, growth cone motility and
myelination [31-33]. The nuclear localization of tau and its ability to
selectively bind double stranded DNA [34,35] has led to suggestions
that tau may play roles in cell cycle regulation/early developmental fate
that are relevant to both AD-associated aberrant cell cycle re-entry and
even certain types of carcinogenesis . An additional new function
– the involvement of a small amount of tau localized to the postsynaptic
density in synaptic plasticity -appears particularly relevant to NDD
pathogenesis mechanisms .
The sudden interest in tau that came with its identification as the
major component of NFTs in the late 1980s produced what might
be called a molecular identity crisis for tau that has had important
consequences. Tau became a “disease protein” and interest in its normal
functions, particularly those functions associated with neuronal development, was largely effaced by the effort to understand the role of
tau in NFT formation and AD pathogenesis. In addition, the absence of
a link between tau and established secretion pathways restricted interest
in tau secretion and tau-related interneuronal disease mechanisms. The
recent broadening of research scope to include intercellular aspects of
tauopathy pathogenesis was prompted by demonstrations that a) A beta
cytotoxicity is largely mediated by tau in both cell culture and murine
model systems [38-40] b) the demonstration of tau secretion and uptake
[19,21,41-43] and extracellular tau toxicity [44-46] and most of all, c) the
application of what might be called the “prionlike hypothesis” [47-49]
to account for what appeared to be transsynaptically connected patterns
of lesion evolution in AD  and other tauopathies . The prior
demonstration by Gloria Lee and co-workers that the amino teminal
“projection” domain mediates interactions with key signal transduction
elements such as fyn kinase  now also appears to be a key element
in our newly expanded appreciation of the roles played by tau in NDD
pathogenesis, since tau-fyn interactions, especially in dendrites 
now appear to play an essential role in mediating A beta toxicity as well
. This, together with links between tau dendritic localization and
dendritic cytoskeletal disruption [19,41,54,55], localized tau secretion
[19,41] and synaptic dysfunction  illustrate the importance of tau
localization and possibly of neuronal polarity disruption in tauopathy
[57,58]. Finally, demonstrations that N terminal tau fragments can
themselves be toxic and can mediate A beta toxicity [59-62] highlight
the need to link the molecular and systemic studies of prionlike lesion
propagation mechanisms with cellular studies of tau pathobiology.
The meeting (comprising oral presentations from 24 invited
speakers and 34 posters) was organized around the concept of tau as
a “prionlike” protein i.e. capable of communicating toxicity between
cells via interneuronal transfer followed by conformation–altering
interactions with “normal” tau proteins. Many of the presentations
dealt with this topic directly; describing new cellular (Diamond) and/or
rodent models of tau lesion spreading or cellular interactors associated
with tau misfolding and oligomerization. Attempts were made to
integrate aspects of tau function relevant to characteristic features of
non AD tauopathies, such as tau splice variants (Zilka) and in injury
associated tauopathy (Kayed) and argyrophilic grain disease (Rabano).
A major additional theme was directed at imaging and biomarker
related diagnostic development and possible therapeutics (Gozes).
However, nearly half of the presentations were on topics that were only
tangentially related or unrelated to templated misfolding-mediated
lesion spreading of tau. Most of these were directed at the as yet poorly
understood cellular aspects of tauopathy outlined above that will need to
be integrated with the concept of the “prionlike” mechanism of toxicity
and/or lesion spreading at the cellular level before the actual relevance
and contribution of this mechanism to human NDD pathogenesis can
be ascertained. A major advantage of the meeting is that it combined
exponents and modelers of “prionlike” tau lesion spreading (Diamond,
Buee, Kayed, Zilka, Sergeant, Duff, Avila) with a range of investigators
involved in non “prionlike” aspects of tau pathobiology, including key
contributors to what we now know about both tau aggregation and
hyperphosphorylation (Sahara, Spillantini, Sergeant, Iqbal, Alonso,
Mandelkow, Mudher, Avila), tau/MT interactions (Gozes, Alonso,
Iqbal), and other NDD relevant aspects of tau function such as A-beta
interactions (Gotz, Bloom, Perry) exosomal (Hall) and non-exosomal
modes of tau secretion and uptake (Avila, Hanger, Diamond, Duff),
tau localization (Gotz, E. Mandelkow), toxicity (E. M. Mandelkow)
and turnover (Cuervo, Myeku). While most of the presentations
involved studies using conventional cellular and rodent models,
exponents of other models that have made important contributions to
our understanding of diverse aspects of tauopathy, such as the fruit fly
(Mudher) and the sea lamprey (Hall) were also present. Finally, several
presentations described recent advances in imaging (Sahara, Duff),
immunotherapy (Sigurdssen) and functionally directed therapeutic approaches (Kosik, Gozes, Bhat). In the end, a broad sample of the
current perspectives, method and research foci in the field were
reflected among the invited speakers and attendees, despite the tight
organizational focus of the meeting.
Current studies of tau associated dysfunction in NDD are finally
starting to integrate our hitherto fragmented view of tauopathy
pathogenesis into a more comprehensive picture of how diverse tau
functions associated with NDD-associated events (e.g. oligomerization,
cell cycle re-entry, apoptotic changes, signal transduction pathway
disruption, polarity loss, lesion spreading etc.) can account for global
as well as cellular features of neurodegenerative tauopathies. Somewhat
ironically, this synthesis has been occurring as a single novel idea – that
of toxicity transfers via protein: protein conformational templating –
has taken hold in the field. This state of affairs was exemplified by the
Cantablanco tau meeting of 2013, which went significantly beyond
its stated focus on “prionlike” speading mechanisms in tauopathy
and crystallized many of the disparate threads of interest and effort
that currently make up international tau and tauopathy-directed
basic research. This broad, integrative approach combined with a well defined, but not exclusive, focus on a plausible common disease
mechanism of great current interest seems likely to foster synergistic
interactions among the participants and represents a distinct break
from historical norms in the field. It is both a hopeful metaphor for the
current state of tauopathy research and (in the eyes of this participant)
a worthy “template” for future progress.
Perhaps we “tauists” are finally applying the lessons we learned
during the “war” .
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