**6. Neuroinflammation in Parkinson disease**

PD is the second most prevalent neurodegenerative disease after AD. These diseases are prototypic examples of the clinical manifestations of pathological brain aging and are charac‐ terized by cognitive deterioration—the first—and movement disorder—the latter. About 3% of the population over 65 years old will develop PD and these patients will be affected by a combination of movement disorders -i.e. parkinsonian sindrome- cognitive and neuropsychi‐ atric symptoms, and autonomic function impairment [113]. Neuropathological studies on AD, ALS and PD brains have demonstrated the presence of protein aggregates that have been considered as a central part of neurodegenerative process.

In PD there is a specific damage to neurons in substantia nigra pars compacta in midbrain. Degeneration of nigrostriatal connections is responsible for motor, cognitive, and psychiatric symptoms.

There is a complex interaction between genetic susceptibility and external factors that deter‐ mines damage to dopaminergic neurons of the substantia nigra that is responsible for PD development.

Increased permeability of blood-brain barrier and neurovascular dysfunction has been linked to the risk of PD as has been suggested by positron emission tomography (PET) and neuro‐ pathology studies. This may be related to increased leakage of systemic inflammatory molecules into the midbrain, activation of microglia, and death of dopaminergic neurons [114]. The role of systemic inflammatory response in PD is supported by increased activation of peripheral lymphocytes and increased levels of serum cytokines—that is, TNF-α, IL-2, IL-6, and regulated on activation, normal T cell expressed and secreted (RANTES) protein in PD patients [114].

A role of adaptive immune response is also supported by increase of MHC II in ventral midbrain astrocytes and microglia as an inflammatory response to MPTP in a murine PD model [115]. On the other hand, MHC II null mice showed less MPTP-induced neuronal death, reduced invasion of astrocytes and microglia, and no elevation in IFN-γ and TNF-α [115].

Since astrocytes constitute near half of central nervous system cells and they may perform a function as immunocompetent cells producing a variety of cytokines. Aquaporin-4 (AQP4) is upregulated in astrocytes in several inflammatory conditions including PD. Sun et al. have described that AQP4 knockout mice treated with MPTP showed increased basal and inducible expression of NF-κB and increased gliosis and they propose that AQP4 may modulate neuroinflammation via regulating release of proinflammatory cytokines and ATP by astro‐ cytes which in turn further activates microglia [116].

There are some features that explain localized damage in substantia nigra pars compacta (SNpc); neurons in the area are particularly susceptible to oxidative damage as they operate under high oxidant conditions due to reduced levels of the anti-oxidant glutathione and increased iron content. On the other hand, there is a high density of microglia cells that mediates neuroinflammatory processes [114]. Oxidative stress induces the generation of ROS by microglia that become activated. DJ-1, the product of PARK 7 gene, is a gene associated with hereditary PD, works as a repressor of phosphatase and tensin homolog (PTEN)—a tumor suppressor gene—and has important functions in cellular antioxidant response. Since loss-offunction mutations of DJ-1 have been associated with PD, Meiser et al. described that loss of DJ-1 impairs antioxidant response and induces weak constitutive microglia activation in mouse microglia [117].

Microglia may become activated by a wide variety of damage signals that include toxins, pathogens, endogenous proteins or products generated by dying neurons. The constitutive expression of proinflammatory cytokines IL-1β, TNF-α, IL-2, IL-6, and IFN-γ has been demonstrated in PD patients in postmortem brain analyses as well as in serum and cerebro‐ spinal fluid *in vivo* [114].

Activation of microglia by dying neurons may result in a vicious circle of neuroinflammation and neurodegeneration [114]. Some of these substances liberated by degenerating neurons include α-synuclein aggregates, neuromelanin, adenosine triphosphate (ATP), and matrix metalloproteinase-3 (MMP-3) [114].

In PD there is a specific damage to neurons in substantia nigra pars compacta in midbrain. Degeneration of nigrostriatal connections is responsible for motor, cognitive, and psychiatric

There is a complex interaction between genetic susceptibility and external factors that deter‐ mines damage to dopaminergic neurons of the substantia nigra that is responsible for PD

Increased permeability of blood-brain barrier and neurovascular dysfunction has been linked to the risk of PD as has been suggested by positron emission tomography (PET) and neuro‐ pathology studies. This may be related to increased leakage of systemic inflammatory molecules into the midbrain, activation of microglia, and death of dopaminergic neurons [114]. The role of systemic inflammatory response in PD is supported by increased activation of peripheral lymphocytes and increased levels of serum cytokines—that is, TNF-α, IL-2, IL-6, and regulated on activation, normal T cell expressed and secreted (RANTES) protein in PD

A role of adaptive immune response is also supported by increase of MHC II in ventral midbrain astrocytes and microglia as an inflammatory response to MPTP in a murine PD model [115]. On the other hand, MHC II null mice showed less MPTP-induced neuronal death, reduced invasion of astrocytes and microglia, and no elevation in IFN-γ and TNF-α [115]. Since astrocytes constitute near half of central nervous system cells and they may perform a function as immunocompetent cells producing a variety of cytokines. Aquaporin-4 (AQP4) is upregulated in astrocytes in several inflammatory conditions including PD. Sun et al. have described that AQP4 knockout mice treated with MPTP showed increased basal and inducible expression of NF-κB and increased gliosis and they propose that AQP4 may modulate neuroinflammation via regulating release of proinflammatory cytokines and ATP by astro‐

There are some features that explain localized damage in substantia nigra pars compacta (SNpc); neurons in the area are particularly susceptible to oxidative damage as they operate under high oxidant conditions due to reduced levels of the anti-oxidant glutathione and increased iron content. On the other hand, there is a high density of microglia cells that mediates neuroinflammatory processes [114]. Oxidative stress induces the generation of ROS by microglia that become activated. DJ-1, the product of PARK 7 gene, is a gene associated with hereditary PD, works as a repressor of phosphatase and tensin homolog (PTEN)—a tumor suppressor gene—and has important functions in cellular antioxidant response. Since loss-offunction mutations of DJ-1 have been associated with PD, Meiser et al. described that loss of DJ-1 impairs antioxidant response and induces weak constitutive microglia activation in

Microglia may become activated by a wide variety of damage signals that include toxins, pathogens, endogenous proteins or products generated by dying neurons. The constitutive expression of proinflammatory cytokines IL-1β, TNF-α, IL-2, IL-6, and IFN-γ has been demonstrated in PD patients in postmortem brain analyses as well as in serum and cerebro‐

symptoms.

30 Update on Dementia

development.

patients [114].

mouse microglia [117].

spinal fluid *in vivo* [114].

cytes which in turn further activates microglia [116].

Microglia can get activated by pathologically altered forms of α-synuclein in PD, but also in other synucleinopathies such as dementia with Lewy bodies and multiple systems atrophy. Microglia activation gives raise to a balance between clearance of α-synuclein by phagocytosis via TLR4 microglia and neuronal dysfunction and neurodegeneration via oxidative stress and proinflammatory cytokine production by microglia [113].
