Juan
Carlos Polanco, Jürgen Götz
INTRODUCTION
This
EMBO News&views paper is about recent progress on how amyloid‐β
(Aβ) and tau exacerbate Alzheimer's disease (AD) at a subcellular
level.
A
link has been established between type 2 diabetes and AD: insulin
dysregulation occurs in brain tissue from AD patients and mouse
models for AD.
mTOR
(the protein kinase mammalian target of rapamycin) is a key molecule
in the insulin signalling: its hyperactivation mediates insulin
resistance, which is one cause of type 2 diabetes.
AD
is characterized by the aggregation of two molecules: the peptide
amyloid‐β (Aβ) and the protein tau, which impair neuronal
function. This accumulation has been linked to lysosomal dysfunction.
Lysosomes
and mitochondria both malfunction in various human diseases. This
makes sense in the light of the discovery of mitochondria–lysosome
membrane contact sites. This could mean that these two organelles
also cooperate in physiological conditions.
RECENT
DEVELOPMENTS
In
the same issue of EMBO, Norambuena et al provide evidence that
oligomeric forms of Aβ (Aβos) disrupt the functional crosstalk
between lysosomes and mitochondria, thereby contributing to the early
stages of AD.
It
was already known that mitochondrial dysfunction impairs lysosomal
structure and function in a manner that depends on the levels of
mitochondrial ROS.
Norambuena
et al have provided evidence that that there is also an opposite
information flow, with mitochondria receiving signals from lysosomes.
This mechanism is dependent on mTORC1, a multiprotein signalling
complex nucleated by mTOR and bound to the cytosolic side of
lysosomes. This mTORC1 was shown to be activated by insulin and amino
acids, leading to what the authors have called “nutrient‐induced
mitochondrial activation (NiMA)”,
This
lysosomal signalling was strongly inhibited by Aβos and was found to
depend on the activation of mTORC1 by a mechanism that requires tau.
Indeed, NiMA was not blocked by Aβos in tau knockout neurons.
This
reinforces the view that tau facilitates the formation of signalling
complexes affecting neuronal function. Future research could be
targeted at the isolation and characterization of these putative
complexes.
