Multifunctional Effect of Human Serum Albumin Reduces Alzheimer's Disease Related Pathologies in the 3xTg Mouse Model

J Alzheimers Dis. 2016;50(1):175-88. doi: 10.3233/JAD-150694.


Alzheimer's disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifests simultaneously, eventually leading to cognitive impairment and death. No treatment is currently available; however, an agent addressing several key pathologies simultaneously has a better therapeutic potential. Human serum albumin (HSA) is a highly versatile protein, harboring multifunctional properties that are relevant to key pathologies underlying AD. This study provides insight into the mechanism for HSA's therapeutic effect. In vivo, a myriad of beneficial effects were observed by pumps infusing HSA intracerebroventricularly, for the first time in an AD 3xTg mice model. A significant effect on amyloid-β (Aβ) pathology was observed. Aβ1-42, soluble oligomers, and total plaque area were reduced. Neuroblastoma SHSY5Y cell line confirmed that the reduction in Aβ1-42 toxicity was due to direct binding rather than other properties of HSA. Total and hyperphosphorylated tau were reduced along with an increase in tubulin, suggesting increased microtubule stability. HSA treatment also reduced brain inflammation, affecting both astrocytes and microglia markers. Finally, evidence for blood-brain barrier and myelin integrity repair was observed. These multidimensional beneficial effects of intracranial administrated HSA, together or individually, contributed to an improvement in cognitive tests, suggesting a non-immune or Aβ efflux dependent means for treating AD.

Keywords: Albumin; Alzheimer’s disease; blood-brain barrier; cognitive impairment; inflammation; myelin; therapy.

MeSH terms

  • Albumins / therapeutic use*
  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / toxicity
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Blood-Brain Barrier / drug effects
  • Brain / drug effects
  • Brain / pathology*
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology
  • Disease Models, Animal
  • Drug Delivery Systems
  • Encephalitis / drug therapy
  • Encephalitis / etiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Neuroblastoma / pathology
  • Neuropsychological Tests
  • Peptide Fragments / toxicity
  • Presenilin-1 / genetics
  • tau Proteins / genetics


  • Albumins
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Calcium