Amyloid pathology and synaptic loss in pathological aging

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Both AD and PA contain amyloid plaques dominated by amyloid beta (A beta) peptides. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and A beta peptide patterns between AD and PA. Two cohorts of post-mortem brain tissue were investigated. In the first, consisting of controls, PA, AD, and familial AD (FAD) individuals, synaptic proteins extracted with tris(hydroxymethyl)aminomethane-buffered saline (TBS) were analyzed. In the second, consisting of tissue from AD and PA patients from three different regions (occipital lobe, frontal lobe, and cerebellum), a two-step extraction was performed. Five synaptic proteins were extracted using TBS, and from the remaining portion A beta peptides were extracted using formic acid. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. The amyloid plaque load was increased in AD compared with PA, and the relative amount of A beta 40 was higher in AD while for A beta 42 it was higher in PA. In AD loss of synaptic function was associated with increased plaque load and increased amounts of A beta 40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of A beta.

Automated summary

This study compared synaptic protein levels, amyloid plaque load, and A beta peptide patterns between AD and PA. It found that AD patients had lower levels of synaptic proteins, increased amyloid plaque load, and higher A beta 40 levels compared to PA cases. This suggests that synaptic function is preserved in PA cases even in the presence of A beta.