We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-␤ (A␤) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport A␤ into endosomes and lysosomes, and AD monocytes do not efficiently clear A␤ from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport A␤ to endosomes and lysosomes, and monocytes of these subjects clear A␤ in AD brain sections. Upon A␤ stimulation, mononuclear cells of normal subjects up-regulate the transcription of ␤-1,4-mannosyl-glycoprotein 4-␤-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of A␤ may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon A␤ stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of A␤, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.amyloid-␤ ͉ phagocytosis ͉ endocytosis ͉ MGAT3 siRNA A ccording to the amyloid-␤ (A␤) hypothesis, amyloidosis occurring in the brain of patients with Alzheimer's disease (AD) by fibrillar A␤ 1-42 and 1-40 (1) and A␤ oligomers (2) is a leading cause of neurodegeneration in AD (3). Macrophages and microglia are the innate immune cells responsible for clearance of pathogens and waste products. We have shown that blood-borne monocyte/ macrophages of AD patients migrate across the blood-brain barrier into AD brain but are defective in clearance of A␤ in neuritic plaques (4), and they overexpress cyclooxygenase-2 and inducible NO synthase (4). Resident microglia in AD brain display markers of inflammation (5, 6), phagocytosis (7), and proinflammatory but not prophagocytic genes (8). However, most microglia invading A␤ plaques in transgenic mouse models are bone marrow-derived, not resident microglia (9). Thus, the brains of AD patients and transgenic mice seem to display inflammatory responses by microglia and defective A␤ clearance by blood-borne macrophages. Consequently, the defective innate immune system of AD patients might be a culprit in brain amyloidosis leading to brain inflammation.The mechanisms of neurodegeneration produced by abnormally folded proteins, A␤, and phosphorylated remain an enigma (10).The pathogenesis of neurodegeneration in AD involves the impact of polymorphic proteins, such as amyloid precursor...

The defective clearance of amyloid-β (Aβ) in the brain of Alzheimer's disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Aβ but only inefficient clearance of Aβ deposits. Neurons and neuronal nuclei, respectively, express interleukin-1β and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology of Aβ clearance, we examined Aβ phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Aβ followed by Aβ degradation or export. AD monocytes show poor differentiation and only surface uptake of Aβ and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Aβ clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system.

In both HIVE and AD, blood-borne activated monocyte/macrophages and lymphocytes appear to migrate through a disrupted blood-brain barrier. The lacunae around macrophages in amyloid-beta plaques but not in vessel walls are consistent with the ability of macrophages to phagocytize and clear amyloid-beta deposits in vitro.

No abstract

The numbers of immune-activated brain mononuclear phagocytes (MPs) affect the progression of human immunodeficiency virus (HIV)-1-associated dementia (HAD). Such MPs originate , in measure , from a pool of circulating monocytes. To address the mechanism(s) for monocyte penetration across the bloodbrain barrier (BBB) , we performed cross-validating laboratory , animal model , and human brain tissue investigations into HAD pathogenesis. First , an artificial BBB was constructed in which human brain microvascular endothelial and glial cells-astrocytes, microglia , and/or monocyte-derived macrophages (MDM)-were placed on opposite sides of a matrixcoated porous membrane. Second , a SCID mouse model of HIV-1 encephalitis (HIVE) was used to determine in vivo monocyte blood-to-brain migration. Third , immunohistochemical analyses of human HIVE tissue defined the relationships between astrogliosis , activation of microglia , virus infection, monocyte brain infiltration , and ␤-chemokine expression. The results , taken together , showed that HIV-1-infected microglia increased monocyte migration through an artificial BBB 2 to 3.5 times more than replicate numbers of MDM. In the HIVE SCID mice, a marked accumulation of murine MDM was found in areas surrounding virus-infected human microglia but not MDM. For human HIVE , microglial activation and virus infection correlated with astrogliosis, monocyte transendothelial migration , and ␤-chemokine expression. Pure cultures of virus-infected and activated microglia or astrocytes exposed to microglial conditioned media produced significant quantities of ␤-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces ␤-chemokine-mediated monocyte migration in HAD. (Am J Pathol 1999, 155:1599 -1611)