Chronic sialidase effects on amyloid aggregation and associated pathology

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Alzheimer’s disease is characterized by the aggregation of β-amyloid (Aβ) protein in the brain, widespread neurodegeneration, and cognitive decline. Our work focuses on amelioration of Alzheimer's pathology by reducing or simplifying the major brain gangliosides and the pro-apoptotic ganglioside GD3. Gangliosides are glycosphingolipids richly expressed in brain tissue. We have previously shown that knocking out the gene that codes for GD3S (St8sia1) drastically reduces Aβ aggregation and oxidative stress, and prevents memory deficits in mice carrying mutant human transgenes for amyloid precursor protein (App) and presenilin 1 (Psen1), genes known to cause Alzheimer's disease. In addition, primary neurons from GD3S knockout mice are resistant to Aβ-induced cell death. However, GD3S is absent from birth in these mice, and they lack many of the gangliosides critical for normal brain development. The objective of the proposed studies is to determine whether in vivo degradation of b-series gangliosides and GD1a is as effective as knocking out GD3S in alleviating features of Alzheimer's disease in the 5xFAD mouse model of Alzheimer's disease. The general hypothesis of the proposed research is that vibrio cholerae sialidase (VCS) will successfully reduce plaque formation, block cell death, and prevent memory impairments in adult mutant mice. In the proposed experiments, VCS will be chronically administered to assess efficacy in 5xFAD transgenic mice. Cognition, anxiety, and sensorimotor function will be assessed in all mice. Post-mortem analyses will include a full complement of assays to assess Alzheimer-related neuropathology and cell death. Successfully reducing amyloid burden, cell death, and memory impairment in the transgenic mice may provide insight into new treatment strategies for Alzheimer’s disease—treatments that could reduce or prevent neurodegeneration and dementia in Alzheimer patients.