Intraneuronal Abeta42 accumulation in Down syndrome brain

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Alzheimer's disease (AD) and Down syndrome (DS) brains exhibit amyloid-beta (Abeta) plaques, inflammation, and neurofibrillary tangles (NFTs).
• Evidence suggests neurons are a source of Abeta.
• The temporal sequence of Abeta accumulation and associated pathologies in DS is not fully understood.

Purpose of the Study:

• To investigate the temporal dynamics of intraneuronal Abeta accumulation in Down syndrome brains.
• To determine the relationship between intracellular Abeta, extracellular plaque formation, inflammation, and NFT development in DS.

Main Methods:

• Immunohistochemical examination of temporal cortex sections from 70 DS cases (ages 3-73).
• Utilized antibodies targeting Abeta N-terminus, Abeta40 C-terminus, and Abeta42 C-terminus.
• Assessed immunoreactivity (IR) for Abeta species, gliosis, and NFT formation.

Main Results:

• Intracellular Abeta42 immunoreactivity was detected in very young DS patients, declining with age.
• Abeta40 and N-terminal Abeta were not significantly detected intracellularly.
• Extracellular Abeta40 was observed in mature plaques in older cases.
• Intracellular Abeta42 accumulation preceded extracellular plaque deposition.
• Inflammation and NFT formation followed Abeta deposition in DS temporal cortex.

Conclusions:

• Amyloid-beta 42 (Abeta42) accumulates intracellularly in neurons in Down syndrome prior to extracellular Abeta deposition.
• The maturation of extracellular Abeta deposits triggers inflammatory responses.
• Neurofibrillary tangle formation occurs subsequent to Abeta deposition in the DS temporal cortex.