Immune-Inflammatory Responses in the Clinical Progression of Alzheimer's Disease Dementia

Giulio Maria Pasinetti

Mount Sinai School of Medicine

Funded in June, 2002: $300000 for 7 years


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Immune-Inflammatory Responses in the Clinical Progression of Alzheimer's Disease Dementia

Using surface-enhanced laser desorption ionization technology, we identified and purified two novel metal binding protein biomarkers (among others) of 11.7 and 13.3 kDa respectively, whose content was elevated in the cerebral spinal fluid of early Alzheimer's disease (AD) dementia cases, in comparison to cognitively normal controls. Further analysis indicated that the levels of both these proteins correlated with the levels of ß-amyloid (Aß) content and the extent of AD dementia assessed by Mini-Mental State Exam in the same patients. Additionally, we found that these changes were mitigated by treatment with anti-inflammatory drug treatment. Following purification and protein sequence analysis using a combination of mass spectrometry and protein database search, we found that the two biomarkers corresponded to known proteins involved in immune inflammatory responses, namely cystatin C and psoriasin.

Cystatin C is known to be a key component in the regulation of humoral and cell mediated immunity in the periphery, and has recently been found to possess similar functions in astroglia and dendritic cells. Psoriasin is a novel CD4+T lymphocyte chemotactic protein involved in the inflammatory skin disorder psoriasis. Recent studies have indicated a genetic association of a cystatin C gene polymorphism with late-onset AD.  Cystatin has also been reported to exhibit altered expression (in the CSF) in AD, as well as other amyloid and non-amyloid based neuroinflammatory disorders. Currently there is no published evidence linking psoriasin to neuroinflammatory disorders. However, it is believed that psoriasin serves as an immune responsive protein in psoriasis and other inflammatory skin disorders (in atopic dermatitis, mycosis fungoides, Darier's disease, and lichen sclerosus et atrophicus).

The primary goal of this application is to continue exploring the relationship between these two immuno-inflammatory biomarkers with AD dementia, specifically their temporal pattern of expression in the presence and absence of anti-inflammatory drug treatment, and their involvement in Aß peptide generation. We will test the hypothesis that immuno-inflammatory events related to cystatin C and psoriasin may be involved in the onset and progression of AD dementia. The proposed studies will provide novel information on diagnosis, treatment, and possibly prevention of early AD dementia