Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain
Introduction
Individuals with Down syndrome (DS) develop Alzheimer disease (AD) pathology in a progressive age-dependent manner [26], [34], [35], [68] and as such, are at high risk for the development of dementia [29], [33]. Clinical signs of dementia are more commonly observed when individuals are over 50 years of age [4], [29], [49], [63]. By age 40 years, however, all individuals with DS have neuropathological changes including senile plaques and neurofibrillary tangles consistent with AD [35], [67], [68]. Senile plaques contain the β-amyloid peptide that is derived from a longer precursor protein, β-amyloid precursor protein (APP), the gene for which is on chromosome 21. In the most common form of DS, trisomy 21, chromosome 21 (21q21.2) is present in triplicate and leads to overexpression of APP [52]. However, despite life-long overexpression of APP in brain and in peripheral lymphocytes [47], [52], Aβ accumulation in plaques does not typically begin until after the age of 30 years [35]. However, Aβ within diffuse plaques and compact plaques has also been observed occasionally in the temporal cortex of individuals under 40 years (i.e. in childhood, teens and in early adulthood) [30], [31]. These reports suggest that APP processing may lead to the production of nonamyloidogenic fragments at younger ages and shift to favor production of Aβ in later years.
APP is cleaved by alpha-secretase leading to a nonamyloidogenic pathway [56]. The amyloidogenic pathway leading to Aβ production occurs by sequential cleavage of APP by β-secretase and subsequently by γ-secretase [43], [56]. β-secretase has now been identified as beta-site APP cleaving enzyme or BACE [65]. Once Aβ is cleaved from APP it may first appear in soluble form either within neurons or in the extracellular space. Higher levels of soluble Aβ are observed in DS fetal brain and in brains from adults up to 61 years of age than in tissue from controls [61]. Thus, individuals with DS exhibit higher levels of soluble Aβ, which may interact with both developmental and aging processes but conversion into more insoluble forms with age may be a critical event related to plaque accumulation. Additionally, Aβ degradation and clearance mechanisms may also be critically involved with the accumulation of plaques in DS with increasing age [16]. To our knowledge, no studies have shown age related increases in insoluble Aβ in the brains of DS subjects nor linked functional changes in secretase activity to Aβ. Further evidence that Aβ and APP processing play a critical role in AD pathogenesis and relevant for DS is a recent report of several families with early onset AD associated with duplication of the APP locus [51]. These individuals develop dementia around the age of 50 years and develop both parenchymal and vascular Aβ deposition.
We hypothesized that age-dependent increases in beta-secretase and/or decreases in alpha-secretase activity may be associated with increased production of amyloidogenic fragments of APP and with Aβ deposition. We predicted prior to the age of 30 years, when Aβ typically begins to accumulate in plaques, that secretase activity may be relatively stable. After this age, we hypothesized that secretase activity to show either decreases (alpha-secretase) or increases (beta-secretase). Thus, we assayed secretase activity in the midfrontal cortex of DS cases ranging in age from 5 months to 69 years in comparison to a series of control cases. Last, we measured Aβ1–40 and Aβ1–42 in formic acid soluble fractions of frozen frontal cortex to link Aβ to secretase activity. The midfrontal cortex was selected because it is vulnerable to age-associated AD pathology in DS and may be an early site of Aβ pathogenesis in DS [22].
Section snippets
Subjects
Frozen tissue blocks from the midfrontal cortex were obtained from a total of 35 individuals (22M, 13F) with DS ranging in age from 5 months to 69 years of age. A series of 18 control cases (11M, 7F) ranging in age from 5 months to 69 years were used as an age-matched group for comparison. An additional series of “oldest old” autopsy cases were also included to provide a broad range of ages for normal aging and included eight subjects ranging in age from 93 to 100 years (4M, 4F). DS and young
Results
As shown in Table 1, the average age of the control cases (mean = 36.9, S.E. = 5.6) was not significantly different from the DS cases (mean = 37.5, S.E. = 3.5), (t(51) < 1, p = 0.93). Control cases over the age of 90 years were of an average age of 95.8 years (S.E. = 0.75). The post mortem interval in the DS cases (mean = 12.4, S.E. = 1.4) was higher than in the controls (mean = 8.65, S.E. = 1.2) and the difference approached significance (t(51) = 1.70, p = 0.095). This is due to the long post mortem intervals in the
Discussion
In the most common form of DS, trisomy 21, three copies of chromosome 21 (21q21.2) leads to the overexpression of APP in brain and in peripheral lymphocytes [47], [52]. As a consequence, plasma Aβ is significantly higher in individuals with DS (17–58 years) than in age-matched controls [8], [38], [55]. However, reports of further age-dependent increases in plasma Aβ in DS are variably reported as increased [38] or unchanged [8], [55]. In CSF, there is an age dependent decrease in Aβ42 that may
Acknowledgements
Funding supported by UCI ADRC P50 AG16573, NIH/NIA AG21912, NIH/NIA AG 21055, “My Brother Joey Clinical Neuroscience Fund”, UW ADRC NIA P50 AG 05136-21 and a College of Medicine Committee on Research and Graduate Academic Program Award. The authors appreciate the helpful comments on the manuscript provided by Drs. Jorge Busciglio and Dr. Wayne Poon (UCI) and Drs. Paul Murphy and Jeffery Keller (U Kentucky). We are grateful to the families and individuals with Down syndrome that made this work
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2021, Molecular and Cellular NeuroscienceCitation Excerpt :Plaque density is however higher in DS brain (Hof et al., 1995; Head et al., 2016). Post-mortem analyses have shown increased levels of both insoluble Aβ40 and Aβ42 with age, with a particularly steep increase in Aβ40 leading to a decrease in the Aβ42/40 ratio after the age of 40 (Nistor et al., 2007), i.e., the age when signs of worsening of cognitive function and behavior are most often observed (Sinai et al., 2018). Immunoreactivity believed to be fibril-specific has been associated also with early, diffuse, Aβ deposits (Sarsoza et al., 2009).