Why Alzheimer’s patients have no memory loss when the disease starts


Image: A section of brain cortex with hyperphosphorylated tau showing in black; (inset) a model of the PRPc protein

Alzheimer’s is a neurodegenerative disease characterized by a gradual loss of memory and other mental dysfunction, as neurons die and different areas of the brain atrophy. The disease is the most common form of dementia and appears most frequently in the over-65s (1.5 cases per 1000 people a year in Europe, reaching 69.2 cases per 1000 in the over 90s). There are two stages: the initial one where symptoms aren’t clear, and a second phase with well-defined symptoms.

Alzheimer’s can be attributed to two major events that can happen in the brain; the presence of extracellular aggregates, mostly a compound known as beta-amyloid peptide, which forms plaques; and the accumulation of a very phosphorylated form of the protein tau, which forms small tangles inside affected neurons. Until now, it was known that the formation of these tau tangles in neurons depends on the toxicity of the beta-amyloid peptide, but it the mechanisms of this interaction between the two wasn’t understood.

The researchers – who worked in collaboration with members of CIBERNED, the Centre for Molecular Biology in Madrid, and the Institute of Neuropathology IDIBELL-Bellvitge University Hospital – describe the relationship between beta-amyloid peptide oligomers and tau phosphorylation and the presence of another protein, the cellular prion protein (PrPc), in affected neurons. The results show that when the levels of PrPc are high, the levels of phosphorylated tau protein inside the cell are lower, even if the beta-amyloid peptide oligomers are present.

“Previous studies had looked at the levels of PrPc in advanced stages of the disease,” explains Dr. José Antonio del Río, group leader of the Molecular and Cellular Neurobiotechnology group at IBEC and professor in the UB’s Department of Cellular Biology. “But our new study shows, both in mice and human brains affected by Alzheimer’s, an increase in protein PrPc during the early, asymptomatic stages of the disease. However, these levels of PrPc decrease as the disease progresses.”

When PrPc levels are low, the amount of tau – as well as its phosphorylated form that makes the tangles inside the cell – increases, contributing to the brain deterioration observed in Alzheimer’s. “As a result, it is reasonable to draw the conclusion that the overexpression of PrPc seen at the beginning of the disease is part of the protective response of the nervous system in an attempt to suppress the progress of Alzheimer’s”, says Dr. del Río. “Consequently, patients with Alzheimer’s do not show memory deficits until the later stages of the disease.”

Reference article: Cristina Vergara, Lara Ordóñez-Gutiérrez, Francisco Wandosell, Isidre Ferrer, José Antonio del Río, Rosalina Gavín (2014). “Role of PrPC expression in tau protein levels and phosphorylation in Alzheimer’s disease evolution”. Molecular Neurobiology, Volume 51, Issue 3, pp 1206-1220
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