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as to the impact of TLR4 on disease development, microglia, activated astrocytes, and Aβ protein in the
since TLR4 was both protective and harmful in these brain. [101,102] Effects of TLR4 knock-out on behavior
models. Since TLR4 is suggested to be protective in or disease progression have not been reported. The
the context of α-synuclein overexpression, TLR4 increase of Aβ protein in the brain of TLR4 animals
-/-
seems likely to be protective in the context of PD, could be due to a lack of TLR4-mediated Aβ clearance,
since α-synuclein misfolding and aggregation is a potentially by microglia. [102,103]
hallmark of the disease. The harmful contribution
of TLR4 to MPTP-induced PD seems to suggest that Cell culture data support a pro-inflammatory role
TLR4 might have a negative impact on the health for microglia, and implicate microglia-induced
of a subgroup of PD patients who suffer from toxin- inflammation in neuronal degeneration. Mouse
induced PD (for instance after exposure to MPTP or microglia initiate an inflammatory and phagocytic
rotenone). Therefore, TLR4 appears mostly protective response to aggregated Aβ through TLR4, resulting
in the context of PD, but it might be harmful in the in microglia-mediated neuronal death. [82,99] Microglia
context of toxin-induced PD. need TLR4 to initiate LPS-stimulated Aβ uptake, in
fact they trigger a stronger inflammatory response to
Similar to TLR2, microglia form a link between TLR4 Aβ in combination with LPS. [84,102]
and PD. Microglia are necessary for LPS-induced
degeneration of rat cortical neurons in cell culture Neurons themselves respond to Aβ and AD-related
since these neurons themselves do not express peroxidation product HNE through TLR4, resulting
TLR4, and nitric oxide and superoxide seem to be in apoptosis. [40] Since little is known about the
at least partially responsible for microglial-induced role of neuronal TLR4 in AD, it is important to
neurodegeneration. [97,98] On the other hand, microglial start exploring the function of this receptor in
TLR4 is necessary for the neuroprotective endocytosis animal models and in patient tissue, in a way that
of α-synuclein. Microglia activated with α-synuclein differentiates glial-mediated TLR4 responses from
[96]
downregulate TLR4, disabling any neuroinflammatory neuronal responses, for instance by selective knock-
positive feedback loop, but also reducing the ability down of TLR4 in neurons in AD mouse models.
of the microglia to take up α-synuclein from their Collectively, it seems that TLR4 induces an immune
[77]
environment. These results are contradictive and response in AD through pro-inflammatory cytokines,
whether TLR4 is protective or injurious in PD is still a aimed at the removal of Aβ by microglial uptake,
matter of debate. The balance between the contribution but also phagocytosis of neurons by microglia.
of microglial TLR4 to neuroinflammation and the Insufficient removal of Aβ results in an increase of Aβ
endocytosis of α-synuclein might eventually determine in the extracellular space, the subsequent activation
whether this receptor is protective or harmful to the of microglia and astrocytes, and neuronal apoptosis.
surrounding neurons. TLR4 is a promising target In light of this hypothesis, it is also interesting to note
for future PD research. The role of TLR4 during PD the similarity in the role of microglial TLR4 in AD and
can be both beneficial and harmful, and the factors PD, where this receptor is responsible for the uptake
determining the outcome need to be investigated of disease-specific aggregated protein and initiation of
in more detail. It seems that neuronal TLR4 could neuroinflammation, possibly causing neuronal death.
be protective, but the role of microglial TLR4 is still
not fully understood. Resolving this debate could Stroke
potentially lead to approaches aimed at turning TLR4 has both beneficial and detrimental effects in
harmful TLR4 responses into protective ones. stroke models. Neurons of I/R treated mice show TLR4
upregulation, a first clue that TLR4 is involved in stroke-
AD induced brain damage. [29,37] Paradoxically, mice treated
One of the first lines of evidence suggesting that TLR4 with low dose systemic LPS two days before I/R injury
might be involved in AD pathology comes from two had smaller infarct sizes and less neuroinflammation
studies where a TLR4 polymorphism was found to in the brain, while TLR4 mice had less stroke-induced
-/-
be protective against late onset Alzheimer’s disease brain damage and less neurological deficits after I/R
in the Italian population and glial cells surrounding treatment. [29,104] Although these results do not suggest a
Aβ plaques showed increased TLR4 expression in beneficial or harmful role of TLR4 in stroke, the data are
post mortem brain tissue. [99,100] In a genetic AD mouse not mutually exclusive. TLR4 stimulation before stroke
model TLR4 knock-out reduced the expression of seems to be protective, while TLR4 stimulation during
TNFα and chemokine (C-C motif) ligand 4 (also known stroke seems detrimental. This hypothesis is supported
as macrophage inflammatory protein-1β) in cortex by in vitro experiments. Increased TLR4 activity does
homogenate, while increasing the amount of activated not increase neuronal death, and TLR4 stimulation

32 Neuroimmunol Neuroinflammation | Volume 3 | Issue 2 | February 15, 2016