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LABORATORY RESEARCH INTERESTS

  1. Innate immune dysfunction in Alzheimer’s disease patients and development of a diagnostic test

Alzheimer’s disease (AD) patients show defective clearance of amyloid-beta (Aβ) by the innate immune system and suffer saturation of the brain with Ab. In our studies of over 100 AD patients, we have   shown defective Ab phagocytosis by fluorescence microscopy and flow cytometry, reduced expression of surface proteins, in particular CD44 and MHC Class II HLA DR, and increased propensity to apoptosis. Immune biomarkers distinguish two types of AD patients’ macrophages, a majority (named “Type I”) display defective Aβ phagocytosis, transcriptional down regulation of the genes MGAT-III and Toll-like receptors-2 and -3, and gene transcriptional up regulation by curcuminoids. In a minority of patients (named “Type II”), macrophages show normal transcription at baseline but down regulation by curcuminoids. The results of flow cytometric testing may be helpful for screening (most cognitively normal subjects have normal results) and for detection of AD risk on longitudinal follow-up.

  1. Alzheimer’s disease therapeutics by Vitamin D3 and curcuminoids

Crosssectional studies of vitamin D3 levels suggest that insufficient levels increase risk of dementia. We have shown that in both Type I and Type II macrophages, 1,25D3 strongly stimulates Aβ phagocytosis and clearance while protecting against apoptosis.  Certain synthetic curcuminoids in combination with 1,25D3 had additive effects on phagocytosis in Type I but not Type II macrophages. The 1,25D3 genomic antagonist analog MK, inhibited 1,25D3 but not curcuminoid effects, suggesting that 1,25D3 acts through the genomic pathway.

  1. Role of innate immune pathogenesis in cerebral amyloid angiopathy

Neuronal accumulation of oligomeric amyloid-beta (Ab) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Ab stress to neurons by immigration into the brain and phagocytosis of Ab. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Ab by macrophages. Both AD and normal macrophages were inhibited in Ab export across the blood-brain barrier due to adherence of Ab-engorged macrophages to the endothelial layer. In comparison to normal subjects’ macrophages, AD macrophages ingested and cleared less Ab, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Ab. Confocal microscopy of stained AD brain sections revealed oligomeric Ab in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Ab  in plaques and microvessel walls. After incubation with AD brain sections, normal subjects’ monocytes intruded into neurons and uploaded oligomeric Ab. These results suggest macrophages of AD patients shuttle Ab from neurons to vessels where their apoptosis may release fibrillar Ab, contributing to cerebral amyloid angiopathy.

  1. Inflammatory and immune responses in patients with amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by motor paralysis due to degeneration of spinal cord neurons. Our results suggest that in the ALS spinal cord, activated macrophages and mast cells attack neurons. In peripheral blood of ALS patients, mononuclear cells are activated (at baseline and especially after SOD stimulation) and produce increased cytokines IL-1beta, IL-6, TNF-alpha etc.