Elsevier

Neurobiology of Aging

Volume 28, Issue 10, October 2007, Pages 1493-1506
Neurobiology of Aging

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

https://doi.org/10.1016/j.neurobiolaging.2006.06.023 Get rights and content

Abstract

Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months–69 years) and in 26 controls (5 months–100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Aβ) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Aβ degradation and clearance.

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

References (69)

  • A. Hirayama et al.

    Characteristic developmental expression of amyloid β40,42 and 43 in patients with Down syndrome

    Brain Dev.

    (2003)
  • C.A. Lemere et al.

    Sequence of deposition of heterogeneous amyloid beta-peptides and APOE in Down syndrome: implications for initial events in amyloid plaque formation

    Neurobiol Dis

    (1996)
  • J.B. Leverenz et al.

    Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis

    Exp Neurol

    (1998)
  • D.M.A. Mann

    The pathological association between Down syndrome and Alzheimer disease

    Mech Ageing Dev

    (1988)
  • D.M.A. Mann et al.

    The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome

    J Neurol Sci

    (1989)
  • E. McGowan et al.

    Abeta42 is essential for parenchymal and vascular amyloid deposition in mice

    Neuron

    (2005)
  • P.D. Mehta et al.

    Increased plasma amyloid β protein 1-42 levels in Down syndrome

    Neurosci Lett

    (1998)
  • K. Motonaga et al.

    Elevated expression of beta-site amyloid precursor protein cleaving enzyme 2 in brains of patients with Down syndrome

    Neurosci Lett

    (2002)
  • M.P. Murphy et al.

    Presenilin 1 regulates pharmacologically distinct gamma-secretase activities. Implications for the role of presenilin in gamma-secretase cleavage

    J Biol Chem

    (2000)
  • J. Nunan et al.

    Regulation of APP cleavage by α–, β– and γ-secretases

    FEBS Lett

    (2000)
  • C. Pallister et al.

    Lymphocyte content of amyloid precursor protein is increased in Down's syndrome and aging

    Neurobiol Aging

    (1997)
  • I. Pinnix et al.

    A novel gamma-secretase assay based on detection of the putative C-terminal fragment-gamma of amyloid beta protein precursor

    J Biol Chem

    (2001)
  • C. Russo et al.

    Amino-terminal modification and tyrosine phosphorylation of [corrected] carboxy-terminal fragments of the amyloid precursor protein in Alzheimer's disease and Down's syndrome brain

    Neurobiol Dis

    (2001)
  • N. Schupf et al.

    Elevated plasma amyloid beta-peptide 1-42 and onset of dementia in adults with Down syndrome

    Neurosci Lett

    (2001)
  • S.E. Stoltzner et al.

    Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease

    Am J Pathol

    (2000)
  • S.J. Tyler et al.

    Alpha- and beta-secretase: profound changes in Alzheimer's disease

    Biochem Biophys Res Commun

    (2002)
  • A. Bush et al.

    Risk factors for dementia in people with Down syndrome: issues in assessment and diagnosis

    Am J Ment Retard

    (2004)
  • A.M. Cataldo et al.

    APP gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of Down syndrome

    J. Neurosci.

    (2003)
  • S. Cavani et al.

    Plasma levels of amyloid β 40 and 42 are independent from ApoE genotype and mental retardation in Down syndrome

    Am J Med Gen

    (2000)
  • P. Das et al.

    Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/-knock-out mice

    J Neurosci

    (2003)
  • B. De Strooper et al.

    Proteolytic processing and cell biological functions of the amyloid precursor protein

    J Cell Sci

    (2000)
  • E. Engidawork et al.

    Selective upregulation of the ubiquitin-proteasome proteolytic pathway proteins, proteasome zeta chain and isopeptidase T in fetal Down syndrome

    J Neural Transm Suppl

    (2001)
  • K. Fabel et al.

    VEGF is necessary for exercise-induced adult hippocampal neurogenesis

    Eur J Neurosci

    (2003)
  • H. Fukumoto et al.

    Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease

    Arch Neurol

    (2002)
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