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11-06-2015 | Alzheimer's disease | News | Article

Early neuronal lysosomal dysfunction could help predict AD

medwireNews: Blood levels of altered lysosomal proteins may help detect preclinical Alzheimer’s disease (AD), researchers report.

“Abnormal levels of the proteins may be useful biomarkers that could help us study early treatments to limit or reverse the damage to brain cells and even prevent the development of the full-blown disease”, said lead researcher Edward Goetzl (UCSF Medical Center, San Francisco, USA) in a press release.

Blood samples from 26 patients with AD showed that three of these proteins, which would normally be eliminated in autolysosomes, were significantly increased compared with samples from 26 matched controls without AD.

Average levels of cathepsin D were 17.7 ng/mL versus 8.35 ng/mL in controls, while respective levels of lysosome-associated membrane protein 1 (LAMP-1) and ubiquitinylated proteins were 1808 pg/mL versus 946 pg/mL and 477 pg/mL versus 225 pg/mL.

Meanwhile mean levels of heat-shock protein 70, which are normally secreted predominantly in exosomes, were significantly lower in AD patients than controls, at 246 pg/mL versus 394 pg/mL.

And for 20 patients who had blood samples taken before and after developing AD, protein levels were similarly abnormal 1 to 10 years before the onset of symptoms and at diagnosis of mild cognitive impairment or dementia, with differences significant on both occasions compared with controls.

Stepwise discriminant modelling of the protein levels, excluding LAMP-1, enabled patients with AD to be distinguished from controls with 100% accuracy and from 16 patients with frontotemporal dementia with 95.8% accuracy.

The researchers suggest that in AD patients neural cellular stress results in exosomes importing lysosomal proteins from dysfunctional autolysosomes rather than secreting them, while neurotoxic proteins cause lysosomal dysfunction that impairs autolysosome biodegradation and increases exosomal cargo.

“These diverse mechanisms of autophagic-lysosomal dysfunction in AD provide new targets for potentially therapeutic agents”, they write in Neurology.

Goetzl believes the results “help us to understand how the brain responds to the developing disease”, but adds that “this is an early study with a small number of patients – these results need to be confirmed with larger studies.”

By Lucy Piper

medwireNews is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2015