Down syndrome (DS) is one of the most common genetic causes of
intellectual disability and is characterized by a number of behavioral as well as
cognitive symptoms. Many of the neuropathological features of early-onset
Alzheimer's disease (AD) including
senile plaques and neurofibrillary tangles (NFTs) are also present in people with DS as a result of triplication of the
amyloid precursor gene on chromosome 21. Evidence suggests that harboring one or both
apolipoprotein E4 (
APOE4) alleles may increase the risk for AD due to the proteolytic cleavage of
apoE4 and a subsequent loss of function. To investigate a role for the
apoE proteolysis in vivo, we compared three autopsy groups; 7 DS with AD neuropathology cases over 40 years, 5 young DS cases without AD pathology under 40 years (YDS) and 5 age-matched control cases over 40 years by immunohistochemistry utilizing an antibody that detects the amino-terminal fragment of
apoE. Application of this antibody, termed the amino-terminal
apoE fragment antibody (nApoECF) revealed labeling of pyramidal neurons in the frontal cortex of YDS cases, whereas in the DS-AD group, labeling with nApoECF was prominent within NFTs. NFT labeling with nApoECF was significantly greater in the hippocampus versus the frontal cortex in the same DS-AD cases, suggesting a regional distribution of truncated
apoE. Colocalization immunofluorescence experiments indicated that 52.5% and 53.2% of AT8- and PHF-1-positive NFTs, respectively, also contained nApoECF. Collectively, these data support a role for the proteolytic cleavage of
apoE in DS and suggest that
apoE fragmentation is closely associated with NFTs.