The role of the immune system in Alzheimer's Disease
KAPINAS K., KAPINA V., NOTARIDIS G.

Alzheimer's disease (AD) as regards its etiology, is considered to be an heterogeneous disease, mainly characterized by aggregation of b-amyloid plaques and inflammatory destruction of neurons.

Several mechanisms, such as genetic predisposition, metabolic disturbances, abnormal protein synthesis and degeneration of neurons, seem to play an important role in the onset and the progression of AD.

B-amyloid () is cytotoxic, thus resulting in overexpression -of acute phase proteins, complement activation, increased production of the fibroblast growth factor and increased production of IL-1. The latter, together with IL-6 as inflammatory cytokines, enhance the inflammatory process in the amyloid plaques, which leads to a disturbance in the synapses and to cell death. B-amyloid of the amyloid plaques in AD activates both the classical, as well as the alternative complement pathway, resulting in a dynamic inflammatory reaction. Specific complement inhibitors could cause the termination or the inhibition of the disease progress.

Senile plaques are characterized by the concentration of Ab peptide, produced by the metabolism of amyloid precursor protein (APP). APP resulting from the genetic mutation in chromosome 21. A protein and protein t, but also apolipoprotein E (ApoE), preseniline 1 resulting from a mutation in chromosome 14 and preseniline 2 resulting from a genetic mutation in chromosome 1 are involved in AD. Prodromal APP substance of B-amyloid, Apo-E, preseniline 1 and preseniline 2, lead to increased biosynthesis and aggregation of b-amyloid in senile plaques.

Apo-E in the brain is formed and secreted mainly by neuroglia and especially by astrocytes. Apo-E affects the survival of neurons, by interfering in the oxidative stress process on a different degree for each isoform. Apo-E connects to , which is transferred from astrocytes to the surface of the neurons.

Activated astrocytes, which are related to senile plaques can separate neurons from senile plaques and produce cytokines and growth factor similar to those produced by microglia. In AD the neurons that are constantly activated by b-amyloid, lose their suppressive ability, if a chronic immune response predominates and which having lost its initial beneficial role, leads to the destruction of tissues and to neuronal death. Constantly activated Microglia, and astrocytes, can destroy the neighboring neurons by the secretion of highly toxic products, like active superoxide radical, nitric oxide, inflammatory cytokines, proteolytic enzymes, complement components or active amino-acids.

Nowadays, AD is considered to be a multifactorial disease and it is predominantly believed that inflammatory immunological factors are involved in its process. This was supported by the observation that patients with rheumatoid arthritis, who were under long treatment with non-steroidal anti-inflammatory drugs (NSAIDS) had a low incidence of AD. In addition, histopathological and molecular surveys support the existence of an inflammatory process in the brain of patients with AD, even from the early stages of the disease. This is strengthened by the presence of activated microglia, proteins that take part in immunological reactions, such as complement proteins and its regulators, inflammatory cytokines (interleukins, 1a, 1b, 6, TNF) and protease inhibitors like a1-antihymothrypsin, a2-macrospherin and other factors of the immune reaction, which accumulate in senile plaques and especially in the core of the amyloid. Activated glial cells surround the Ab, which aggregate and form the so-called "mature senile plaques". Furthermore, cycloxygenase-2 (COX-2), which is responsible for the synthesis of inflammatory prostaglandins is found on the cortex and especially the hippocampus of patients with AD.

NSAIDS are inhibitors of the production of COX-1 and COX-2.

Multifactorial disturbance of neuronal cell function in AD, eventually leads to a certain type of cell death, which is called "apoptosis" or "prescheduled cell death".

Metabolic disturbance of the brain which leads to AD is estimated to begin 10-20 years before the first symptoms of cognitive impairment appear.

Key words: Alzheimer, immunology.