Abstract
The success of future intervention strategies for Alzheimer’s disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia
Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the cerebrospinal fluid (CSF) from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration
We investigated the presence of endosomal proteins in neurological controls (NC) and AD CSF (Table 1, CSF set 1) using Western blot analysis
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The major pathological hallmarks of AD are neurofibrillary tangles composed of hyperphosphorylated tau protein, plaques consisting of aggregated amyloid-b (Ab) peptides and loss of synapses and neurons in defined areas of the brain (Blennow et al 2006). Cerebrospinal fluid (CSF) biomarkers for Ab and tau are used to diagnose AD in research and increasingly in clinical practice. The presence of increased CSF levels of totaltau (T-tau) and phosphorylated tau (P-tau181P) together with lowered levels of Ab1–42 has an 85–95 % accuracy rate for the identification of future AD patients in mild cognitive impairment (MCI) cases (Blennow et al 2010). Additional complementary biomarkers are needed to monitor the progression into AD and to stratify possible subpopulations of AD patients. The success of future intervention strategies for AD will likely rely on an accurate and early diagnosis with subsequent treatment before the brain is irreversibly damaged
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
