In this issue of JEM, Marciniak et al. (https://doi.org/10.1084/jem.20161731)
identify a putative novel function of tau protein as a regulator of
insulin signaling in the brain. They find that tau deletion impairs
hippocampal response to insulin through IRS-1 and PTEN dysregulation and
suggest that, in Alzheimer’s disease, impairment of brain insulin
signaling might occur via tau loss of function.
Alzheimer’s disease (AD) is the leading form of dementia
worldwide. The two major histopathological hallmarks of AD are senile
plaques composed of amyloid-β (Aβ) peptide and neurofibrillary tangles
made of abnormally hyperphosphorylated tau protein. Tau pathology is
important because it correlates with the degree of cognitive impairment
in AD patients. The majority of AD cases are late onset and sporadic,
and many environmental, biological, and genetic factors are thought to
contribute to the disease. Epidemiological studies particularly suggest
that metabolic disorders such as type 2 diabetes (T2D) could be such
factors, as they are associated with a higher risk of AD later in life.
Brain insulin resistance appears to be an early and common feature of AD (for review see Stanley et al., 2016), and AD has been proposed as a “type 3 diabetes” representing a form of diabetes that selectively involves the brain (de la Monte and Wands, 2008).
Our current knowledge on how AD pathologies may alter brain insulin
signaling relies on evidence showing the development of brain insulin
resistance after oligomeric Aβ exposure, thus implicating amyloid
pathology as a major mediator of brain insulin resistance in AD (Bomfim et al., 2012). However, although the impact of insulin dysfunction on tau pathogenesis has been extensively studied (for review see El Khoury et al., 2014), the effects of tau pathology on insulin signaling has never been assessed before.
Tau
is a microtubule binding protein whose most well-known function is to
bind and stabilize microtubules. But it has also been suggested to have
many other functions such as regulation of cell signaling, synaptic
plasticity, and genomic stability (Guo et al., 2017).
Tau pathology in AD is thought to exert its detrimental effects through
a toxic gain of function, but a potential loss of physiological
function might also contribute to some phenotype of the disease. In this
issue, Marciniak et al.
hypothesized that in AD, tau loss of function could alter brain insulin
signaling and partly explain the cognitive and metabolic impairments
observed in AD.
Using mice depleted for MAPT, the tau gene (tau KO mice), Marciniak et al. (2017)
initially identified a reduction of hippocampal long-term depression of
extracellular field excitatory postsynaptic potentials in brain slices
from tau KO mice compared with littermate controls after insulin
treatments. Altered response to insulin was confirmed in the same mice
model ex vivo and in vivo with decreased activation of IRS-1 and AKT
(both implicated in insulin signaling), suggesting brain insulin
resistance in tau KO mice. By taking advantage of coimmunoprecipitation
experiments and bimolecular fluorescence complementation assay, the
authors further evaluated whether tau directly interacts with key
insulin signaling molecules in neuroblastoma cells expressing
non-mutated human tau protein. Unexpectedly, tau did not seem to
interact with either the insulin receptor IRS-1 or with PI3K (p85).
However, tau was found to interact with PTEN, a phosphatase known to
inhibit insulin signaling through the PI3K-Akt pathway. Moreover, Marciniak et al. (2017)
demonstrated that human tau is able to reduce PTEN activity and thus
promote PIP3 production alone or by potentiating the effect of insulin
(see figure).http://jem.rupress.org/content/jem/214/8/2171/F2.medium.jpg
Next, Marciniak et al. (2017)
assessed whether tau deletion alters brain insulin functions.
Interestingly, absence of tau reduced the anorexigenic effect of
intracerebroventricular injection of insulin in tau KO mice. These mice
also developed peripheral hyperinsulinemia and glucose intolerance.
These data confirmed an important role of tau in the regulation of
energy metabolism. Finally, the authors noticed an effect of tau
haplotype on glucose tolerance in published genome-wide association
study (GWAS) data. H1 haplotype is associated with higher risk of
tauopathies (Pittman et al., 2005), and in the study by Marciniak et al. (2017),
patients with H1 haplotype exhibited higher circulating glucose levels
and lower insulin levels during an oral glucose tolerance test,
suggesting that tau impacts peripheral metabolism in humans. Overall,
the in vivo and in vitro results dovetail nicely together and with the
GWAS data to provide compelling evidence that tau can regulate both
brain insulin signaling and peripheral glucose metabolism.
The study by Marciniak et al. (2017)
further addresses a question that has emerged over the last few years
as to whether AD is a cause or consequence of insulin signaling
impairment (Stanley et al., 2016).
Epidemiological studies supported by in vivo and in vitro experiments
establish metabolic problems as risks for AD. However, the study by Marciniak et al. (2017)
is the first assessing whether tau pathology affects brain insulin
signaling in AD. Interestingly, metabolic changes and central insulin
resistance have been reported in other tauopathies such as progressive
supranuclear palsy or corticobasal degeneration (Ahmed et al., 2014; Yarchoan et al., 2014).
This suggests that the alteration of insulin signaling resulting from
the loss of tau function upon tau pathology may explain metabolic
changes in many tauopathies. At the same time, Marciniak et al. (2017)
raise new questions regarding mechanisms underlying the role of tau
protein as a regulator of brain insulin signaling that need
clarification. For instance, the two molecular events suggested to
explain this novel function of tau involved IRS-1 and/or PTEN. Early
studies have in fact reported that total IRS-1 but also IRS-2 are
decreased in the brain of AD patients along with increased
phosphorylated IRS-1 on Ser636/639 and Ser616, which colocalizes and correlates with neurofibrillary tangle deposition and inversely correlates with cognitive score (Ma et al., 2009; Moloney et al., 2010; Talbot et al., 2012).
This is consistent with altered IRS-1 activity in tau KO mice reported
in this issue, whereas the authors could not establish a direct
interaction between tau and IRS-1. Another explanation lies in the
direct interaction between PTEN and tau, which can modulate the PTEN
activity and thus explain decreased responsiveness to insulin in tau KO
mice. Although at the current stage it is still impossible to determine
which of IRS-1 or PTEN is the instrument of tau to regulate brain
insulin signaling, the intervention of these two proteins together in
this process is not to be neglected, especially considering that PTEN
has been shown to act as tyrosine phosphatase for IRS-1 in vitro (Shi et al., 2014). Nonetheless, the finding by Marciniak et al. (2017)
that tau has insulin signaling regulator functions in the brain is
remarkable, as it further expands the knowledge about AD and brain
insulin resistance.
However, some of the results of this
study need independent confirmation in other tau KO models. Indeed, the
tau KO model used here is not a true KO, as it was produced by
insertion of EGFP in exon 1 of MAPT, and a fusion protein with the first 31 amino acids of tau followed by EGFP is expressed (Tucker et al., 2001).
Whether some of the results might stem from the production of this
fragment in the absence of functional murine tau will need to be
clarified. This also raises the question as to which region of tau is
mediating the effects observed. The repeat region is involved in
microtubules binding and stability, whereas the projection domain
mediates some of tau signaling functions (Guo et al., 2017).
The region or regions where PTEN binds and the region or regions
important for the regulation of brain insulin sensitivity might be the
same or might be different.
Similarly, and as mentioned by Marciniak et al. (2017),
it would be important to address the sensitivity of central and
peripheral insulin in a conditional KO mice model because tau is present
in the pancreas and could even modulate the secretion and the
transcription of insulin (Neuville et al., 1995; Maj et al., 2016).
Peripheral injections of insulin in tau KO mice could provide important
elements for the understanding of this new function of tau outside of
the brain. Finally, the confirmation of these results in a mouse model
that exhibits tau pathology will be necessary to support the hypothesis
of tau loss of function involvement in brain insulin signaling
impairment in AD, although it is not clear whether the mouse models of
tauopathies available have prominent tau loss of function.
To conclude, the study by Marciniak et al. (2017)
not only identifies a new function of tau protein as a modulator of
brain insulin signaling, but also highlights potential mechanistic
explanation whereby alteration of insulin signaling would occur in AD
via tau loss of function.
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