Age and sex are major risk factors in Alzheimer’s disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 mice and in post-mortem tissue from AD patients. Changes in genes that are indicative of microglial activation were preferentially increased in cells from female APP/PS1 mice and cells from males and females were morphological, metabolically and functionally distinct. Microglia from female APP/PS1 mice were glycolytic and less phagocytic and associated with increased amyloidosis whereas microglia from males were amoeboid and this was also the case in post-mortem tissue from male AD patients, where plaque load was reduced. We propose that the sex-related differences in microglia are likely to explain, at least in part, the sexual dimorphism in AD.

No abstract

Background and Purpose: Chronic inflammation may play a role in the pathogenesis of Parkinson's disease (PD). Noradrenaline is an endogenous neurotransmitter with anti-inflammatory properties. In the present investigation, we assessed the immunomodulatory and neuroprotective efficacy of pharmacologically targeting the CNS noradrenergic system in a rat model of PD.Experimental Approach: The impact of treatment with the β 2 -adrenoceptor agonists clenbuterol and formoterol was assessed in the intranigral LPS rat model of PD. The immunomodulatory potential of formoterol to influence the CNS response to systemic inflammation was also assessed.Key Results: LPS-induced deficits in motor function (akinesia and forelimb-use asymmetry) and nigrostriatal dopamine loss were rescued by both agents. Treatment with the noradrenaline reuptake inhibitor atomoxetine reduced striatal dopamine loss and motor deficits following intranigral LPS injection. Co-treatment with the β 2adrenoceptor antagonist ICI 118,551 attenuated the protective effects of atomoxetine. Systemic LPS challenge exacerbated reactive microgliosis, IL-1β production, dopamine cell loss in the substantia nigra, nerve terminal degeneration in the striatum, and associated motor impairments in animals that previously received intranigral LPS. This exacerbation was attenuated by formoterol treatment. Conclusion and Implications:The results indicate that pharmacologically targeting β 2 -adrenoceptors has the propensity to regulate the neuroinflammatory phenotype in vivo and may be a potential neuroprotective strategy where inflammation contributes to the progression of dopaminergic neurodegeneration. In accordance with this, clinical agents such as β 2 -adrenoceptor agonists may prove useful as immunomodulatory agents in the treatment of neurodegenerative conditions associated with brain inflammation.

Degeneration of the locus coeruleus noradrenergic system is thought to play a key role in the pathogenesis of Parkinson's disease (PD), whereas pharmacological approaches to increase noradrenaline bioavailability may provide neuroprotection. Noradrenaline inhibits microglial activation and suppresses pro-inflammatory mediator production (e.g., tumor necrosis factor-α, interleukin-1β & inducible nitric oxide synthase activity), thus limiting the cytotoxicity of midbrain dopaminergic neurons in response to an inflammatory stimulus. Neighbouring astrocyte populations promote a neurotrophic environment in response to β2-adrenoceptor (β2-AR) stimulation via the production of growth factors (e.g., brain derived neurotrophic factor, cerebral dopamine neurotrophic factor & glial cell derived neurotrophic factor which have shown promising neuroprotective and neuro-restorative effects in the nigrostriatal dopaminergic system. More recent findings have demonstrated a role for the β2-AR in down-regulating expression levels of the human α-synuclein gene SNCA and relative α-synuclein protein abundance. Given that α-synuclein is a major protein constituent of Lewy body pathology, a hallmark neuropathological feature in Parkinson's disease, these findings could open up new avenues for pharmacological intervention strategies aimed at alleviating the burden of α-synucleinopathies in the Parkinsonian brain. In essence, the literature reviewed herein supports our hypothesis of a tripartite neuroprotective role for noradrenaline in combating PD-related neuropathology and motor dysfunction via (1) inhibiting nigral microglial activation & pro-inflammatory mediator production, (2) promoting the synthesis of neurotrophic factors from midbrain astrocytes and (3) downregulating α-synuclein gene expression and protein abundance in a β2-AR-dependent manner. Thus, taken together, either pharmacologically enhancing extra-synaptic noradrenaline bioavailability or targeting glial β2-ARs directly makes itself as a promising treatment option aimed at slowing/halting PD progression.

The results provide evidence that clenbuterol elicits anti-inflammatory effects, suppresses the peripheral acute phase response and reduces the infiltration of neutrophils and apoptotic response to acute IL-1β-induced brain injury. Suppression of both the central and peripheral response following clenbuterol administration may contribute to its protective properties following brain injury.

No abstract

Many studies implicate microglia in the pathogenesis of Alzheimer’s disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators and it is now known that microglia with this secretory phenotype exhibit other adaptations including in their morphology, function, and metabolism. AD, like many neurological disorders, demonstrates a sex bias and recent evidence indicates that the sexual dimorphism in microglial function, which has been recognized for many years in early development, persists into adulthood and aging. Here, we demonstrate sex-related differences in microglia from post mortem tissue of male and female AD patients and a marked increase in the number of dystrophic and rod-shaped microglia in tissue from female AD patients compared with males. Furthermore, there was an increase in iron-laden microglia in tissue from female AD patients and this has been reported to reflect mitochondrial changes. To address this further, we assessed changes in microglia from male and female APP/PS1 mice and demonstrate that iron accumulation in microglia is increased to a greater extent in tissue prepared from females compared with males. This was associated with altered expression of genes coding for proteins that modulate mitochondrial function. The findings suggest that sex-related differences in the severity and perhaps incidence of AD may, at least in part, arise from sexual dimorphism in microglia.

Neuroinflammation is a contributory factor underlying the progressive nature of dopaminergic neuronal loss within the substantia nigra (SN) of Parkinson's disease (PD) patients, albeit the role of astrocytes in this process has been relatively unexplored to date. Here, we aimed to investigate the impact of midbrain astrocytic dysfunction in the pathophysiology of intra‐nigral lipopolysaccharide (LPS)‐induced experimental Parkinsonism in male Wistar rats via simultaneous co‐injection of the astrocytic toxin L‐alpha‐aminoadipic acid (L‐AAA). Simultaneous intra‐nigral injection of L‐AAA attenuated the LPS‐induced loss of tyrosine hydroxylase‐positive (TH+) dopamine neurons in the SNpc and suppressed the affiliated degeneration of TH+ dopaminergic nerve terminals in the striatum. L‐AAA also repressed LPS‐induced nigrostriatal dopamine depletion and provided partial protection against ensuing motor dysfunction. L‐AAA abrogated intra‐nigral LPS‐induced glial fibrillary acidic protein‐positive (GFAP+) reactive astrogliosis and attenuated the LPS‐mediated increases in nigral S100β expression levels in a time‐dependent manner, findings which were associated with reduced ionized calcium binding adaptor molecule 1‐positive (Iba1+) microgliosis, thus indicating a role for reactive astrocytes in sustaining microglial activation at the interface of dopaminergic neuronal loss in response to an immune stimulus. These results indicate that midbrain astrocytic dysfunction restricts the development of dopaminergic neuropathology and motor impairments in rats, highlighting reactive astrocytes as key contributors in inflammatory associated degeneration of the nigrostriatal tract.