Oral immunization with soybean storage protein containing amyloid β4‐10 prevents spatial learning decline

Abstract

AbstractBackgroundAmyloid‐β protein (Aβ) 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 Aβ amyloidosis has been proposed as a mean to block the pathological cascade. We generated a transgenic plant‐based vaccine, a soybean storage protein containing Aβ4‐10, named Aβ+, for oral Aβ immunization.MethodOne mg of Aβ+ or control protein (Aβ‐) with 10 mg cholera toxin subunit B was orally administered via a catheter to TgCRND8 mice once a week from 9 weeks. Extended Morris water maze tests for 10 consecutive days were examined every 4 weeks. Mice were analyzed at 23 weeks (Aβ+ n = 9, Aβ– n = 11), 43 weeks (Aβ+ n = 7, Aβ– n = 6), and 59 weeks (Aβ+ n = 6, Aβ– n = 7).ResultAβ+ immunization raised both anti‐Aβ antibodies and cellular immune responses. Plasma from Aβ+ treated mice showed staining of Aβ oligomers. Spatial learning decline was prevented in the Aβ+ immunized group from 21 weeks. In Tris‐buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aβ species from Aβ monomer, low to high molecular weight Aβ oligomers, and Aβ smears had different solubility in TgCRND8 brains. Aβ oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aβ oligomers in SDS extracts and Aβ smears in FA fraction of the Aβ+ treated group. There was significant inhibition of histological Aβ burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid‐β protein precursor was not different between Aβ+ and Aβ‐ groups. No evidence of amyloid‐related inflammatory angiopathy was observed.ConclusionAβ+ oral immunization could be a promising, cheap, and long‐term safe disease‐modifying therapy to prevent the pathological process in AD.