![]() ![]() SNAP-25 is responsible for docking and fusion to the plasma membrane during vesicular exocytosis, a process which in turn synaptotagmin-1 controls and triggers via its Ca 2+ sensitivity (Mohrmann et al., 2013 Südhof, 2004). SNAP-25, on the other hand, is a t-SNARE protein that exists as two alternatively spliced isoforms: SNAP-25A and SNAP-25B (Irfan et al., 2019). Synaptotagmin-1 is a vital protein for neurotransmitter release in hippocampal neurons due to its function as a calcium-sensor vesicle protein (Courtney et al., 2019). To quantify synapse loss in living patients, biomarkers reflecting the synaptic pathology are needed and we have previously shown that synaptotagmin-1 and synaptosomal-associated protein 25 (SNAP-25) are two emerging presynaptic biomarkers (Brinkmalm, Brinkmalm, Honer, Frölich, et al., 2014 Clarke et al., 2019 Galasko et al., 2019 Tible et al., 2020). ![]() Moreover, the synapses are dysfunctional before they visibly degenerate, both in the form of abnormal morphology and alterations in the synaptic vesicle machinery (Overk & Masliah, 2014). In AD brains, the synapse loss has been estimated to exceed 40% in certain brain regions (DeKosky et al., 2002). Initially, Aβ accumulates in the brain in the form of plaques, followed by tangle formation and synaptic loss and, finally, mainly amnestic symptoms arise (Jack et al., 2013b). The finding has sparked a debate on whether this might be due to protective factors preventing deleterious effects on neuronal function by the amyloid pathology, or if they are simply cases of preclinical AD.ĭue to the slowly progressing nature of AD, the pathologies appear at least 20 years before clinical manifestations (Jack et al., 2013a). This is known as either pathological aging (PA) or cognitively unimpaired with amyloid pathology (CU-AP) (Kvartsberg et al., 2019). Yet, based on the current neuropathological staging, they typically do not reach the amyloid plaque load required to qualify pathologically as AD (Montine et al., 2012 Thal et al., 2002). However, there are patients without cognitive impairment that also display the pathological hallmarks of AD. Another prominent feature of AD is early synaptic pathology, which also correlates with cognitive decline (Terry et al., 1991). Pathological hallmarks of AD include the presence of amyloid plaques and neurofibrillary tangles, consisting of abnormally aggregated amyloid β (Aβ) peptides and tau protein, respectively. It is the most common cause of dementia and as of 2018, 50 million people were estimated to live with AD (Patterson, 2018). tris(hydroxymethyl)aminomethanebuffered salineĪlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline.Matrix-assisted laser desorption/ionization.cognitively unimpaired with amyloid pathology. ![]() In AD loss of synaptic function was associated with increased plaque load and increased amounts of Aβ40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of Aβ. The amyloid plaque load was increased in AD compared with PA, and the relative amount of Aβ40 was higher in AD while for Aβ42 it was higher in PA. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. Five synaptic proteins were extracted using TBS, and from the remaining portion Aβ peptides were extracted using formic acid. 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. 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. Two cohorts of post-mortem brain tissue were investigated. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and Aβ peptide patterns between AD and PA. ![]() Both AD and PA contain amyloid plaques dominated by amyloid β (Aβ) peptides. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. ![]()
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