Alzheimer disease (AD) involves glial inflammation associated with amyloid plaques. The role of the microglial cells in the AD brain is controversial, as it remains unclear if the microglia form the amyloid fibrils of plaques or react to them in a macrophage-phagocytic role. Also, it is not known why microglia are preferentially associated with some amyloid plaque types. This review will provide substantial evidence to support the phagocytic role of microglia in the brain as well as explain why microglia are generally associated with specific plaque types that may be explained through their unique mechanisms of formation. In summary, the data presented suggests that plaque associated microglial activation is typically subsequent to specific amyloid plaque formations in the AD brain.

Deposits of amyloid β‐protein (Aβ) form the cores of the pathological plaques which characterize Alzheimer's disease. The mechanism of formation of the deposits is unknown; one possibility is failure of a clearance mechanism that would normally remove the protein from brain parenchyma. This study has investigated the capacity of the central nervous system (CNS) phagocytes, microglia cells, to clear exogenous Aβ1–42 from their environment. Cultured microglia from adult rat CNS have a high capacity to remove Aβ from serum‐free medium, shown by immunoblotting experiments. Aβ from incubation medium was attached to the cell surface and could be identified by immunocytochemistry at the light or electron microscopic (EM) level; by EM, Aβ also appeared in phagosome‐like intracellular vesicles. Light microscopic immunocytochemistry combined with computer‐assisted image analysis showed that cells accumulated Aβ within 24 hr. from culture medium containing from 1 to 20 μg/ml Aβ. Microglial accumulation of Aβ was substantially reduced in the presence of fetal bovine serum. Addition of the protease inhibitor leupeptin to incubation medium with serum resulted in accumulation of Aβ in a membrane‐bound intracellular compartment, but not at the cell surface. The increase in intracellular accumulation in the presence of the protease inhibitor indicates a microglial capacity for intracellular degradation of Aβ in the absence of inhibition. The change from predominantly cell‐surface accumulation in serum‐free medium to predominantly intracellular accumulation with serum may be explained by the presence in serum of carrier proteins that complex with Aβ and target it to cell surface receptors capable of stimulating endocytosis. Microglia were also cultured on unfixed cryostat sections of human brain tissue containing Alzheimer's plaques. Very little Aβ from the tissue was accumulated by the cells, although cultured microglia were found in direct contact with anti‐Aβ immunopositive plaques. Possibly Aβ in tissue sections was complexed with other proteins which either inhibited its uptake by microglia or enhanced its proteolysis, preventing cellular accumulation of immunostainable Aβ. The results indicate that cultured microglia effectively remove Aβ from tissue culture medium and from the surface of the dish and concentrate monomer and aggregates of Aβ either on the cell surface or intracellularly. This process may be modified by proteins present in Alzheimer's brain sections. © 1996 Wiley‐Liss, Inc.

The extracellular matrix component, s-laminin, is a homologue of the B1 subunit of laminin. S-laminin is concentrated in the synaptic cleft at the neuromuscular junction and contains a site that is adhesive for motor neurons, suggesting that it may influence neuromuscular development. To ascertain whether s-laminin may also play roles in the genesis of the central nervous system, we have examined its expression in the brain and spinal cord of embryonic and postnatal rats. S-laminin was not detectable in synapse-rich areas of adults. However, s-laminin was present in discrete subsets of three laminin-containing structures: (1) In the developing cerebral cortex, laminin and s-laminin were expressed in the subplate, a transient layer through which neuroblasts migrate and cortical afferents grow. Both laminin and s-laminin disappeared as embryogenesis proceeded; however, laminin was more widely distributed and present longer than s-laminin. (2) In the developing spinal cord, laminin was present throughout the pia. In contrast, s-laminin was concentrated in the pia that overlies the floor plate, a region in which extracellular cues have been postulated to guide growing axons. (3) In central capillaries, s-laminin appeared perinatally, an interval during which the blood-brain barrier matures. In contrast, laminin was present in capillary walls of both embryos and adults. To extend our immunohistochemical results, we used biochemical methods to characterize s-laminin in brain. We found that authentic s-laminin mRNA is present in the embryonic brain, but that brain-derived s-laminin differs (perhaps by a posttranslational modification) from that derived from nonneural tissues. We also used tissue culture methods to show that glia are capable of synthesizing "brain-like" s-laminin, and of assembling it into an extracellular matrix. Thus, glia may be one cellular source of s-laminin in brain. Together, these results demonstrate that s-laminin is present in the developing central nervous system, and raise the possibility that this molecule may influence developmental processes.