Structural and functional relationships between the immune and central nervous systems in Alzheimer's disease

Abstract

AbstractAn intact blood–brain barrier (BBB) is a prerequisite to maintaining functional compartmentalization between the neural and immune systems. Only small amounts of immunoglobulins access the internal milieu of the brain, probably via so‐called “functional leaks” existing in the region of the circumventricular organs. However, with aging and disease, globular and other proteins can be found within the cerebrospinal fluid (CSF) because of disruption of perhaps both the BBB and the blood–CSF barrier. There is an increase of lgG, IgA, albumin, and prealbumin in CSF of patients with Alzheimerapos;s disease. The presence of these proteins is taken to be pathognomonic for neuronal impairment, and they are believed to be associated with the amyloid deposits of senile plaques. Our studies have shown that albumins may occur naturally in some CNS neurons. Immunocytochemical studies with antibodies to rat serum albumin have shown the uptake of this serum protein by nerve endings with retrograde transport to perikarya of their cells of origin. Likewise, we have also shown than an endogenous albuminoid substance occurs in arcuate nucleus neurons of the hypothalamus that immunoreact with antibodies to bovine serum albumin. The arcuate nucleus neurons are neurosecretory and have neurohemal endings in contact with blood vessels of the hypothalamohypophysial vasculature. These neurohemal contacts are capable of taking up albumins from the blood for retrograde transport. We, therefore, hypothesize that immunoglobulins may be similarly incorporated by neurons having neurohemal contacts and access the CNS in this and several other ways. We have localized endogenous gammaglobulins in brains of both immunized and nonimmunized rabbits with antisera against rabbit lgG generated in sheep, goat, and mouse. However, serum proteins are also found in neurons without neurohemal contacts. Taken together, albumins, globulins, and other substances may reach the interior milieu of the CNS via: (1) endothelial transcytosis, (2) neurohemal contacts whereby neurons take up blood‐borne substances and retrogradely transport them to their perikarya, (3) circumventricular organs (inter‐ and intraependymal transport), (4) functional leaks at the interface of the circumventricular organs and the brain, (5) a nose–brain pathway, (6) a meningeal pathway, and (7) transsynaptic transport, i.e., substances passed from a neurohemal cell to other connecting neurons.