Add Alzheimer’s disease to the list of autoimmune diseases

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Summary

A sole pathological event leading to Alzheimer’s disease (AD) remains undiscovered in spite of decades of costly research. In fact, it is more probable that the causes of AD are the result of a myriad of intertwining pathologies. However, hope remains that a single awry event could lead to the many pathological events observed in AD brain tissues thereby creating the presentation of simultaneous pathologies. Age-related vascular diseases, which include an impaired blood–brain barrier (BBB), are a common denominator associated with various degrees of dementia, including AD. Recently, a key finding not only demonstrated the anomalous presence of immunoglobulin (Ig) detection in the brain parenchyma of AD tissues but, most importantly, specific neurons that showed degenerative, apoptotic features contained these vascular-derived antibodies. In addition, subsequent studies detected classical complement components, C1q and C5b-9, in these Ig-positive neurons, which also were spatially more associated with reactive microglia over the Ig-negative neurons. Thus, it is possible that the mere presence of anti-neuronal autoantibodies in the serum, whose importance had been previously dismissed, may be without pathological consequence until there is a BBB dysfunction to allow the deleterious effects of these autoantibodies access on their targets. Hence, these observations suggest autoimmunity-induced cell death in AD.

Section snippets

Autoimmunity

The immune system protects the body from potentially harmful substances (antigens), such as foreign microorganisms, toxins, etc. The antigens are presented to cells that make specific antibodies, which ultimately lead to the destruction of the antigens. Unfortunately, these antigens may include “self” antigens leading to inappropriate destruction of normal body tissues (autoimmunity). Hence, normally occurring “harmless” host proteins can now become the target of the immune system. Autoimmunity

Blood–brain barrier dysfunction

As mentioned, autoimmune diseases can include the CNS. However, in order for any of the immunoglobulins to penetrate the brain, there must be an impaired ability to maintain the integrity of the blood–brain-barrier (BBB), a major modulator or filter of nutrient delivery to the CNS that is primarily constructed of endothelial cells and astrocytes [17], [18], [19]. Disturbances in the BBB can occur in head trauma [20], and conditions commonly associated with aging, such as atherosclerosis [21],

The AD autoimmune hypothesis

Immunoglobulins (Ig) have been detected in AD serum, CSF and in amyloid plaques and are associated with vessel-associated amyloid, which has been attributed due to a faulty BBB [38], [40], [46], [47], [48]. Furthermore, several additional reports have demonstrated the presence of Igs in neurons [46], [48], [49], [50] but none of those studies provided specifics as to percentage of neurons positive for Ig in the tissues, subcellular localization of the Ig labeling, and so forth. Unfortunately,

Acknowledgement

We express our deepest gratitude for the many constructive conversations on Alzheimer’s disease research with Drs. Robert Nagele, Daniel Lee, Hoau-Yan Wang and Stanley Belkowski, and for the technical expertise of Brenda Hertzog, Danielle Lawrence, Meghan Towers and Debbie Polkovitch.

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