- Hello, my name is Michael Heneka.
Me and my team are interested
in inflammatory mechanisms in various brain disorders,
including neurodegenerative diseases.
We have been studying
the mechanisms that set the scene for inflammation,
such as locus ceruleus degeneration,
the role of NSAIDS and NSAID mediated protection
in Alzheimer's disease, and ultimately,
got very interested in innate immune activation
through the NLRP3 inflammasome signaling pathway.
Inflammation in Alzheimer's disease,
what is the cause, and what is the meaning,
and why this should be a future research focus?
So, to consider the meaning of an inflammatory response
in Alzheimer's disease,
we have to go back and think
about what the innate immune system,
which drives most of this response,
has been evolutionarily developed for.
And actually, this is the defense of our body to
challenges from outside by fungi,
by bacteria, and by viruses.
So, these innate immune cells, which we call malate cells,
and which include microglial cells,
which represent the brain�s innate immune system,
are actually equipped with pattern recognition receptors
on their surface,
which sends structures that are foreign to them,
and then they illicit an inflammatory reaction,
which is one part releasing inflammatory mediators,
the other part, which is
a phagocytic clearance response.
So, happens to be the fact that
some of the bacteria we know very well,
including Escherichia coli, Staph aureus,
and Salmonella typhimurium,
carry beta-sheet structured amyloids,
very similar to those, as they deposit
in the brains of Alzheimer patients,
on their surface by nature,
which means that if the malate cells
by a pattern recognition,
receptor ligation
sense these structures, they respond in the same way
because that's their evolutionary program.
Now if microglial cells become activated, they are not only
releasing a lot of inflammatory mediators,
they also stop doing a lot of beneficial
things for our brain, including generation and secretion of
trophic factor, synaptic scaling and pruning,
which is necessary to keep neuronal networks going.
Now inflammation has two major consequences,
one is a functional consequence, we know that
the release of these inflammatory mediators, including
A1 beta, TNF alpha, nitric oxide, or other cytokines,
is able to functionally impair neuronal network
activity,
and a prominent example is the suppression of
long-term potentiation in the hippocampus.
While LDP is not equivalent to memory,
it's an important factor to memory consolidation
and long-term storage of information in our brain,
so if that's suppressed we could
conclude that the presence of inflammation impairs
the memory functioning.
Now, after or in parallel to the functional impairment,
there are structural consequences.
So, inflammation of course does not occur alone in
the brains of these patients, there is a cytotoxic activity
as well, and a paper from a long time ago by Cindy Hewitt
and Moses Chao in Neuron in 1996 nicely showed that
inflammation and excitotoxic
stimuli act synergistically and induce neuronal death.
There is an effect on the synaptic structures,
which can be engulfed in a compliment,
three receptor dependent mechanism,
and those synapses which are decoded by C3
are then taken up by microglia.
And that's obviously one of the effects,
which also happens to take place at least in models
of cerebral amyloidosis, which are linked to
Alzheimer's disease.
Now there are other mechanisms by which
inflammatory reactions can impair neuronal survival
including phagocytosis. If neurons do not present do-not-eat-me signals
on their surface, then the immediate reaction
of microglia cells can be to take
those neurons up, even alive, and digest them.
Beyond these direct effects on neurons,
there's a variety of other factors,
so inflammatory molecules in some of
the models have been shown to up-regulate APP processing
especially by increasing beta-secretase one levels,
so fueling into the pro- amyloidogenic pathway,
which would lead to an increase in the concentrations
of beta-amyloid peptides.
At the same time inflammation is able to impair
the phagocytic clearance of a-beta peptides by microglial
cells and maybe other pathways as well.
An intriguing mechanism by which microglia can actually
interfere with beta-amyloid deposition is the activation
of the NLRP3 inflammasome, which leads
to microglial pyroptosis and the release of ASC specks.
And ASC specks are highly aggregating
conglomerates, which
interact with beta-amyloid and actually seed them,
is a fundamental mechanism involved in the seeding
of beta-amyloid pathology in response to the injection
of APP, brain lysate injection
into the hippocampus.
So, obviously this inflammatory molecule
can change the propensity of beta-amyloid to aggregate
and form the seeding core of
plaque deposits.
And that could be replicated in human plaque analysis
as well.