As the medical community desperately seeks more insight into the treatment and prevention of Alzheimer’s disease (AD), early disease biomarkers are incredibly valuable. Not only can these biomarkers gauge disease progression, but they can also, ideally, help identify the disease early and promote effective treatment. Late last year, at the Clinical Trials on Alzheimer’s Disease meeting in Madrid, one promising candidate emerged as an early disease indicator: β-synuclein, a presynaptic protein. Read on to find out more about this protein’s role in indicating AD.
Understanding the Role of β-Synuclein
β-synuclein is a presynaptic protein — in other words, a protein involved in neurotransmission with a role in ensuring functions specific to the presynaptic compartment. It is predominantly expressed in the brain. Patrick Oeckl, a researcher with the German Center for Neurodegenerative Diseases, had previously explored β-synuclein’s connection to AD, finding that the protein’s levels were lower in the brain homogenate from people who had died with sporadic AD. Oeckl’s team also found that β-synuclein amounts increased in both plasma and CSF in the preclinical stages of Alzheimer’s disease. As AD progressed, the levels of the protein increased.
Now, Oeckl’s recent research suggests that β-synuclein starts to increase in the blood more than a decade before any cognitive symptoms arise — specifically, in individuals with a dominantly inherited AD mutation. The research, which could have a markedly positive impact on staging AD, is outlined below.
Evaluating Serum β-Synuclein Concentrations
To identify when and why β-synuclein rises in presymptomatic AD, Oeckl and colleagues used a global resource: the Dominantly Inherited Alzheimer’s Network (DIAN), which hosts samples from individuals with pathogenic APP and presenilin mutations from around the world. Oeckl’s team used a validated mass-spectrometry-based technique to measure β-synuclein in blood samples from this database, including 69 noncarriers, 78 asymptomatic carriers, and 31 symptomatic mutation carriers. They found that, overall, serum concentrations were higher among asymptomatic mutation carriers than noncarriers. Additionally, the concentration of the protein was much higher among carriers who already exhibited memory loss. Finally, reviewing symptom onset data, the team found that serum β-synuclein started to rise around 11 years before an individual’s expected AD onset.
Linking AD Biomarkers
The researchers observed that the protein started to rise in blood around the same time as p-tau205 and total tau in CSF, two important biomarkers for AD. Additionally, Oeckl reported that the protein started rising after cortical PiB-PET scans became positive, but before the advancement of two other markers of AD progression, flagging glucose metabolism and brain atrophy.
Finally, β-synuclein predicted the positivity of amyloid-PET scans — a diagnostic tool for AD — with only 75 percent accuracy, compared to the 99 and 95 percent predictive value of p-tau217 and p-tau181 accumulation, respectively. “This means that β-synuclein is only an indirect marker of amyloid pathology,” Oeckl said.
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While β-synuclein may not be the perfect marker of neurodegeneration, it could have positive implications for the treatment of preclinical AD. Specifically, it could signify future cognitive impairment, allowing individuals to start treatment earlier for better long-term results. It could also be used for trial screening or treatment response monitoring in numerous neurological diseases, including AD.
To study β-synuclein, Scantox Neuro offers in vitro research with the human neuroblastoma cell line SH-SY5Y that stably overexpresses β-synuclein. For controls, other SH-SY5Y cells can be used, overexpressing, e.g., α-synuclein or empty vector. For in vivo experiments, several different genetically modified Alzheimer’s disease mouse models are available that can be stereotactically injected with viral β-synuclein particles. Animals can be evaluated for behavioral differences, such as learning and memory deficits. To evaluate the pathology caused by β-synuclein on brain tissue and SH-SY5Y cells, lysates, CSF, and supernatant can be evaluated for several biomarkers by MesoScale Discovery, western blotting, quantitative RT-PCR, and more. Neurofilament light chain (NF-L) levels are commonly used as a biomarker for neurological disorders. Brain tissue can further be evaluated by immunofluorescent labelling and fluorescent in situ hybridization (FISH). For more information, see Krassnig et al., 2014 or contact us at office-austria@scantox.com.
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