The dietary fatty acids α-linolenic acid (ALA) and linoleic acid (LA) selectively inhibit microglial nitric oxide production.

Alzheimer's disease (AD) is a neurodegenerative disorder without a known cure or effective treatment. Research has identified several modifiable risk factors and suggested preventative measures to reduce the risk of developing AD, including alterations in diet. Polyunsaturated fatty acids (PUFAs) have been shown to regulate inflammatory responses in the central nervous system (CNS), the main site of inflammation in AD. In the CNS, microglia are immune cells responsible for the maintenance of homeostasis. However, in AD, microglia can become adversely activated, causing them to release increased levels of cytotoxins and inflammatory mediators, including nitric oxide (NO) and monocyte-chemoattractant protein (MCP)-1. We assessed the effects of two PUFAs, α-linolenic acid (ALA) and linoleic acid (LA), on select microglial immune functions, since the effects of these dietary fatty acids on neuroimmune responses are not well characterized. In BV-2 mouse microglia activated with lipopolysaccharide (LPS), exposure to LA reduced NO secretion and inducible nitric oxide synthase (iNOS) levels, whereas exposure to ALA reduced NO without a corresponding reduction of iNOS. Neither ALA nor LA altered MCP-1 levels or cytotoxins released by THP-1 human microglia-like cells stimulated with a combination of LPS and interferon (IFN)-γ. Specific receptor antagonists were used to demonstrate that the inhibitory effect of LA on NO secretion did not depend on the free fatty acid receptor (FFAR) 1 or FFAR4. Furthermore, gas chromatography with a flame ionization detector (GC-FID) revealed that exposure to LA or ALA did not alter the fatty acid composition of BV-2 microglia. Our data indicate that regulation of select microglial immune functions by ALA and LA could be one of the mechanisms underlying the observed link between certain dietary patterns and AD, such as reduced risk of cognitive decline and dementia associated with the Mediterranean diet.

Emerging roles of microglial cathepsins in neurodegenerative disease.

Alzheimer's disease (AD) is one of the leading causes of dementia, and its prevalence is expected to increase dramatically due to the aging global population. Microglia-driven neuroinflammation may contribute to the progression of AD. Microglia, the immune cells of the central nervous system (CNS), become chronically activated by the pathological proteins of AD including amyloid-ß peptides (Aß). Such adversely activated microglia secrete mediators that promote inflammation and damage neurons. Cathepsins are proteases that are expressed by all brain cell types, and most of them are found both intra- and extra-cellularly. Microglia express and secrete several different cathepsins, which support various immune functions of microglia, in addition to their involvement in key neuroinflammatory pathways. This review focuses specifically on microglial cathepsins B, D and S, which have been implicated in AD pathogenesis; we identify their roles relevant to microglial involvement in AD pathogenesis. As dysregulated microglial function and neuroinflammation can contribute to AD progression, cathepsins should be considered as potential therapeutic targets for the development of effective AD treatment options. We conclude that the specific inhibition of microglial cathepsin B may lead to neuroprotective outcomes in AD, while the functions of this cysteine protease in neurons appears to be very complex and further studies are required to fully elucidate the pathophysiological role of neuronal cathepsin B. Examination of the CNS roles of cathepsins is limited by the shortage of highly selective inhibitors, with CA-074 being the only available specific cathepsin B inhibitor. We also conclude that non-specific inhibition of aspartic proteases, including cathepsin D, may promote adverse CNS effects, and may not be safe as AD therapeutics. Finally, cathepsin S inhibition has shown promise in preclinical studies due to its neuroprotective and anti-inflammatory effects; however, the many homeostatic roles of cathepsin S must be considered during the subsequent stages of development of cathepsin S inhibitors as AD therapeutics. Discovery of novel, highly selective inhibitors of various cathepsins and their clinical testing are required for the development of effective future AD therapies.

Neuroinflammation as a Common Mechanism Associated with the Modifiable Risk Factors for Alzheimer's and Parkinson's Diseases.

BACKGROUND: Alzheimer's Disease (AD) and Parkinson's Disease (PD) are among the most common causes of dementia, which increasingly contribute to morbidity and mortality worldwide. A common hallmark in the pathogenesis of these two diseases is neuroinflammation, which is initially triggered by the presence of pathological structures associated with these disorders. Chronic neuroinflammation is sustained by persistent and aberrant microglial activation in the brain, which results in damage and death of neighboring cells, including neurons and glial cells. Two types of risk factors contribute to the development of AD and PD: non-modifiable risk factors and modifiable risk factors. Non-modifiable risk factors include genetic susceptibility that increases an individual's risk of developing the disease, whereas modifiable risk factors include a wide variety of health- and lifestyle-related factors that may be altered by changing individual behaviors. METHOD: Ovid Medline and PubMed databases were used to perform an ordered search of the peerreviewed research literature described in this review. RESULTS: This review focuses on four modifiable risk factors including physical inactivity, vascular disease-related conditions, obesity and type two diabetes mellitus, all of which have been identified as risk factors for the development of AD and PD. CONCLUSION: We highlight that control of the modifiable risk factors is a valid approach for managing the increased incidence of AD and PD. We describe neuroinflammatory mechanisms, which are common to AD and PD that may link both these neurodegenerative diseases with the four common modifiable risk factors. Understanding neuroinflammatory mechanisms could help identify novel therapeutic targets for combating these neurodegenerative diseases.