Abstract
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.
Highlights
Down syndrome (DS) is a chromosomal disorder (Trisomy 21) that is caused by nondisjunction resulting in the triplication of the chromosome 21 in the large majority of cases and is the most commonly identified genetic cause of intellectual disability in the United States [1, 2]
Studies suggest harboring the apolipoprotein E4 (APOE4) allele leads to earlier mortality in the DS population that is independent of the risk of dementia [19, 20]
How apoE4 increases the risk for Alzheimer’s disease (AD) is unknown, evidence suggests that the enhanced susceptibility of apoE4 to proteolysis as compared to E2 and E3 may play a critical role leading to loss of function including impaired cholesterol transport and beta-amyloid clearance [21]
Summary
Down syndrome (DS) is a chromosomal disorder (Trisomy 21) that is caused by nondisjunction resulting in the triplication of the chromosome 21 in the large majority of cases and is the most commonly identified genetic cause of intellectual disability in the United States [1, 2]. Risk factors that affect the age of onset of dementia in DS include harboring the APOE4 allele as well as high levels of plasma betaamyloid 1-42 [14]. How apoE4 increases the risk for AD is unknown, evidence suggests that the enhanced susceptibility of apoE4 to proteolysis as compared to E2 and E3 may play a critical role leading to loss of function including impaired cholesterol transport and beta-amyloid clearance [21]. Our findings using the nApoECF antibody in the present study support a role for the proteolytic cleave of apoE with aging and AD in DS and suggest that apoE fragmentation is closely associated with mature NFTs. PMI, postmortem interval in hours; NPD, neuropathological diagnosis; YDS, young Down Syndrome; DS-AD, Down syndrome with Alzheimer’s disease pathology. For all DS-AD cases, the Braak & Braak staging was VI/C
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