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Review
. 2008 Apr;18(2):240-52.
doi: 10.1111/j.1750-3639.2008.00132.x.

Abeta-degrading enzymes in Alzheimer's disease

James Scott Miners  1 , Shabnam Baig, Jennifer Palmer, Laura E Palmer, Patrick G Kehoe, Seth Love
Affiliations
Review

Abeta-degrading enzymes in Alzheimer's disease

James Scott Miners et al. Brain Pathol. 2008 Apr.

Abstract

In Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced Abeta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading Abetain vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOEepsilon4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to Abeta plaque load. Up-regulation of some Abeta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other Abeta-clearance pathways, reductions in the activity of particular Abeta-degrading enzymes may become critical, leading to the development of AD and CAA.

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Figures

Figure 1
Figure 1
Schematic representation of immunocapture‐based fluorometric enzyme activity assay for the measurement of neprilysin (NEP) and insulin‐degrading (IDE) enzyme activity within brain tissue homogenates. The initial immunocapture phase (similar to a standard indirect sandwich ELISA method), prior to the addition of the fluorogenic substrate, allows the specific measurement of NEP enzyme activity in biological tissues separate from other closely related enzymes. Specificity is demonstrated by almost complete inhibition of fluorogenic peptide substrate cleavage in the presence of thiorphan (200 nM), a NEP‐specific inhibitor. The assay combines high sensitivity and specificity and can be adapted to a 96‐well plate format to permit high‐throughput analysis. ELISA = Enzyme‐linked immunosorbent assay.
Figure 2
Figure 2
(A) Insulin‐degrading enzyme (IDE) immunolabeling of neurons within the CA3‐4 and CA2 regions of the hippocampus in control cases and Alzheimer's disease (AD). (B) IDE immunolabeling of neurons is significantly reduced in AD cases (n = 20) compared with age‐matched controls (n = 22) (CA3‐4, P < 0.05 and CA2, P < 0.01). Reductions in IDE neuronal labeling in (C) CA3‐4 and (D) CA2 hippocampal regions are inversely related to Braak tangle stage, APOEε4 genotype, and Aβ plaque load in the temporal lobe. The error bars indicate standard error of mean.
Figure 3
Figure 3
Endothelin‐converting enzyme (ECE‐1) in sections of temporal lobe. A. Immunolabeling ECE‐1 is largely confined to the endothelium. B. Neurons in the CA2 subfield of the hippocampus are strongly immunopositive for ECE‐2.
Figure 4
Figure 4
Angiotensin‐converting enzyme (ACE) protein levels in human post‐mortem cerebrospinal fluid (CSF) samples. The bars in the left chart show the mean values and standard error of the mean in Alzheimer's disease (AD) and control samples. In the right chart the levels are subdivided according to ACE (I/D) genotype. ACE levels (measured by sandwich ELISA) were significantly reduced in AD cases (n = 122) compared with controls (n = 20) (P < 0.05). ACE CSF protein levels were significantly lower in AD cases of I/I genotype (n = 29) (ie, the genotype associated with increased risk of AD) than in D/D (protective genotype) (n = 44) (P < 0.05) and lower, but not significantly, in I/D (n = 34) cases. The number of control CSF samples (I/I = 2, I/D = 8, D/D = 7) in this small series was too small for meaningful assessment of the influence of I/D genotype. ACE CSF levels did not vary according to age or gender but showed a weak positive association with post‐mortem delay (which was adjusted for in the statistical analysis). ELISA = Enzyme‐linked immunosorbent assay. *P < 0.05.
Figure 5
Figure 5
Strong labeling of angiotensin II receptor in arteriolar walls in an Alzheimer's disease (AD) patient with cerebral amyloid angiopathy (CAA).
Figure 6
Figure 6
Steady‐state Aβ levels are maintained by a balance between amyloidogenic processing of amyloid precursor protein (APP) and the removal of soluble Aβ by clearance pathways and enzyme‐mediated degradation. Reduced activity of Aβ‐degrading enzymes favors Aβ accumulation. This probably initiates compensatory upregulation (+) of Aβ‐degrading enzymes, increased degradation of Aβ and reduction (−) in its accumulation. However, reduction in the level or activity of Aβ‐degrading enzymes as a result of age, genetic and environmental factors, and a decline in the efficiency of other Aβ clearance pathways, causes excessive accumulation of Aβ, plaque formation and deposition of Aβ within vessel walls.
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