Inflammatory proteins in the CNS-relation to Alzheimer's disease

Most neurodegenerative disorders are characterised by an inflammatory process in the brain. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the elderly. Activated astrocytes and microglia surrounding the amyloid plaques represent evidence for neuroinflammation in the AD brain. The reactive glial cells produce cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNFalpha), as well as chemokines, complement factors and acute phase reactants.

A constitutive expression of caspase-1 was found in the arcuate nucleus of normal rat brain (Paper I). Caspase-1 was shown to co-exist in these neurons with alpha-melanocytestimulating hormone (alpha-MSH), a neuropeptide with anti-inflammatory properties. This may reflect interactions of alpha-MSH with the formation of IL1beta and IL- 18 through caspase-1 cleavage. Analysis of inflammatory proteins in cerebrospinal fluid (CSF) and serum from patients with mild cognitive impairment (MCI) and severe AD (Paper II), showed no correlation of IL-18 or caspase-1 with the stage of disease. The finding that the levels of soluble IL-1 receptor type II (sIL-1RII) were not altered in MCI or severe AD, unlike previous findings of increased levels in mild to moderate AD, suggests correlation of this protein with stage of disease.

Beta-amyloid (Abeta) peptide, the major component of amyloid plaques, has been shown to activate microglia and stimulate cytokine production. Characterisation of the microglial responses to different forms of Abeta peptides (Paper III) showed that freshly dissolved Abeta1-40, containing a mixture of monomers, oligomers and/or protofibrils, induced an increased secretion of IL-1beta from rat primary microglia, and freshly dissolved Abeta1-42 stimulated the release of IL-1alpha and interferon-gamma (IFN-gamma), whereas API-40 fibrils did not stimulate the release of anyone of the cytokines. Freshly dissolved API40 induced IL-6 release from a human microglial cell line, CHME3 (Paper IV) and reduced cell viability.

Co-incubation with alpha-MSH did not affect the Abeta-induced secretion, but alphaMSH alone was found to stimulate IL-6 release. alpha-MSH did not affect cell viability alone or the reduced viability due to Abeta1-40 The CHME3 cells were shown to express melanocortin receptor (MCR) 1, 3, 4 and 5 (Paper IV). Together with blocking experiments, it would seem that MCR3 and/or MCR5 may mediate the effects of alpha-MSH on IL-6 secretion. Certain cholesterol-lowering drugs, statins, have been shown to exert anti - inflammatory activities. Incubation of the CHME3 cells with atorvastatin and simvastatin, was found to decrease basal secretion of IL-6, whereas only atorvastatin reduced lipopolysaccharide (LPS)- and Abeta-induced secretion (Paper V). Both statins reduced the cell viability, but the effect of simvastatin in combination with either Abeta1-40 or LPS, resulted in an even stronger reduction.

An inflammatory reaction seems to be an early event that is important for the process of developing AD. Finding a marker that can be detected before the first symptoms of AD appear, and interfere with the activation of microglia and the inflammatory process may be a useful therapeutic strategy.

List of scientific papers

I. Lindberg C, Eriksson C, Van Dam AM, Winblad B, Schultzberg M (2004). Neuronal expression of caspase-1 immunoreactivity in the rat central nervous system. J Neuroimmunol. 146(1-2): 99-113.
https://doi.org/10.1016/j.jneuroim.2003.10.047

II. Lindberg C, Chromek M, Ahrengart L, Brauner A, Schultzberg M, Garlind A (2005). Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimers disease. Neurochem Int. 46(7): 551-7.
https://doi.org/10.1016/j.neuint.2005.01.004

III. Lindberg C, Bardyl Selenica ML, Westlind-Danielsson A, Schultzberg M (2005). Beta-amyloid protein structure determines the nature of cytokine release from rat microglia. [Accepted]
https://doi.org/10.1385/JMN:27:1:001

IV. Lindberg C, Hjorth E, Post C, Winblad B, Schultzberg M (2005). Cytokine production by human microglia: effects of beta-amyloid and alpha-melanocyte-stimulating hormone. [Manuscript]

V. Lindberg C, Crisby M, Winblad B, Schultzberg M (2005). Effects of statins on microglia. [Manuscript]