Cerebrospinal Fluid and Plasma Biomarkers in Neurodegenerative Diseases.

Cerebrospinal fluid (CSF) amyloid-ß (Aß)42 and tau are biomarkers for Alzheimer's disease (AD); however, the effects of other neurodegenerative processes on these biomarkers remain unclear. We measured Aß40, Aß42, total tau, phosphorylated-tau, and α-synuclein in CSF and plasma using matched samples from various neurodegenerative diseases to expand our basic knowledge on these biomarkers and their practical applications. A total of 213 CSF and 183 plasma samples were analyzed from cognitively unimpaired subjects, and patients with Alzheimer's disease dementia (ADD), mild cognitive impairment (MCI), non-AD dementias, and other neurological diseases. The CSF/plasma ratios of Aß40 and Aß42 were approximately 25:1. Aß40/42 ratios in CSF and plasma were both 10:1. The CSF total tau/P181tau ratio was 6:1. The CSF/plasma α-synuclein ratio was 1:65. Significantly decreased Aß42 levels and an increased Aß40/42 ratio in CSF in ADD/MCI suggested that these relationships were specifically altered in AD. Increased total tau levels in ADD/MCI, encephalopathy, and multiple system atrophy, and increased P181tau in ADD/MCI indicated that these biomarkers corresponded to neurodegeneration and tauopathy, respectively. Although CSF α-synuclein levels were increased in ADD/MCI, there was no merit in measuring α-synuclein in CSF or plasma as a biomarker. The combination of biomarkers by the Aß40/42 ratio×p181tau reflected specific changes due to the AD pathology in ADD/MCI. Thus, CSF Aß40, Aß42, p181tau, and tau were identified as biomarkers for aggregated Aß associated state (A), aggregated tau associated state (T), and neurodegeneration state (N) pathologies in AD based on the NIA-AA criteria. Overlaps in these biomarkers need to be considered in clinical practice for differential diagnoses of neurodegenerative diseases.

Oral Immunization with Soybean Storage Protein Containing Amyloid-ß 4-10 Prevents Spatial Learning Decline.

Amyloid-ß (Aß) plays a central role in the pathogenesis of Alzheimer's disease (AD). Because AD pathologies begin two decades before the onset of dementia, prevention of Aß amyloidosis has been proposed as a mean to block the pathological cascade. Here, we generate a transgenic plant-based vaccine, a soybean storage protein containing Aß4-10, named Aß+, for oral Aß immunization. One mg of Aß+ or control protein (Aß-) was administered to TgCRND8 mice once a week from 9 weeks up to 58 weeks. Aß+ immunization raised both anti-Aß antibodies and cellular immune responses. Spatial learning decline was prevented in the Aß+ immunized group in an extended reference memory version of Morris water maze test from 21 to 57 weeks. In Tris-buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aß species from Aß monomer, low to high molecular weight Aß oligomers, and Aß smears had different solubility in TgCRND8 brains. Aß oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aß oligomers in SDS extracts and Aß smears in FA fraction of the Aß+ treated group. There was significant inhibition of histological Aß burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid-ß protein precursor was not different between Aß+ and Aß- groups. No evidence of amyloid-related inflammatory angiopathy was observed. Thus, Aß+ oral immunization could be a promising, cheap, and long-term safe disease-modifying therapy to prevent the pathological process in AD.

Aging and APOE-ε4 are determinative factors of plasma Aß42 levels.

OBJECTIVE: The aim of this study was to confirm determinative factors for plasma Aß and its association with cognitive function. METHODS: Fasting plasma Aß40 and Aß42 levels were measured by ELISA in 1019 participants in the Iwaki Health Promotion Project. The relationships between plasma Aß and health-related items, including physical characteristics, cognitive function tests, blood chemistry, and APOE-ε4 genotype were analyzed. RESULTS: The plasma levels of Aß40 and Aß42, and Aß40/42 ratio were found to significantly increase with aging. The age-dependent increase in Aß42 level was significantly suppressed by APOE-ε4. Renal function was an associated factor for the plasma Aß40 level. The plasma Aß42 level and Aß40/42 ratio correlated with cognitive function. INTERPRETATION: Age and APOE-ε4 are major determinative factors of plasma levels of Aß42 and the Aß40/42 ratio. These factors are critical adjustment factors for the usage of plasma Aß as a biomarker of central nervous system amyloidosis.