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. 2010 Jan 12;20(4):794–802. doi: 10.1111/j.1750-3639.2010.00375.x

Changes with Age in the Activities of β‐Secretase and the Aβ‐Degrading Enzymes Neprilysin, Insulin‐Degrading Enzyme and Angiotensin‐Converting Enzyme

J Scott Miners 1, Zoë Van Helmond 1, Patrick G Kehoe 1, Seth Love 1
PMCID: PMC8094798  PMID: 20175776

Abstract

We recently found that insoluble Aβ increases, but soluble Aβ decreases with age in normal brains. We now report the changes in activities of β‐secretase (BACE‐1) and Aβ‐degrading enzymes with age, and their relationships to concentrations of soluble and insoluble Aβ. We measured BACE‐1 activity and the levels and activities of neprilysin (NEP), insulin‐degrading enzyme (IDE) and angiotensin‐converting enzyme (ACE) in normal control brains (16 years–95 years). We also compared the measurements to those in AD. BACE‐1 activity correlated closely with age in controls and was significantly higher in AD. In controls, NEP and IDE activities (but not protein levels) increased with age but ACE activity and level did not. BACE‐1 activity correlated directly with insoluble but inversely with soluble Aβ. IDE activity correlated directly with insoluble Aβ and NEP activity was inversely related to soluble Aβ. ACE level correlated directly with insoluble and inversely with soluble Aβ in controls but not AD. Both Aβ‐synthesizing and ‐degrading enzyme activities increase with age, coinciding with declining soluble Aβ and increasing insoluble Aβ. Further research is needed to establish whether these changes in enzyme activity and Aβ levels are causally related and if so how.

Keywords: Alzheimer's disease, ACE, BACE‐1, β‐secretase, neprilysin, IDE, normal ageing

INTRODUCTION

A neuropathological hallmark of Alzheimer's disease (AD) is the presence of Aβ plaques, composed mainly of Aβ1‐42, and it is the excessive accumulation of Aβ1‐42 that is believed to be responsible for neurodegeneration in AD (16). Aβ accumulation reflects a disturbance in Aβ production and/or clearance, which are normally in balance. Aβ is produced by sequential cleavage of amyloid precursor protein (APP) by β‐secretase (β‐site APP‐cleaving enzyme, BACE‐1) and a γ‐secretase complex that includes presenilin. Aβ removal probably involves multiple processes, including passive drainage, active transport out of the brain, phagocytosis and enzymatic degradation 10, 50, 58. In familial AD, mutations in the APP or presenilin genes are responsible for increased production of Aβ or an increase in the relative amount of Aβ1‐42 (15). The mechanisms underlying the accumulation of Aβ1‐42 in sporadic AD are still unclear.

Aβ exists in a dynamic equilibrium of soluble monomeric, oligomeric, protofibrillar and fibrillar states. The levels of soluble 28, 30, 52, 57, 59, oligomeric Aβ22, 53, 59 and insoluble fibrillar Aβ48, 52, 56, 59 are increased in post‐mortem brain tissue from patients with late‐onset AD compared to age‐matched controls. Although a pathological diagnosis of AD requires the presence of Aβ plaques, which consist predominantly of insoluble fibrillar Aβ, Aβ plaque deposition can occur in the absence of cognitive impairment (8). There is generally a poor correlation between Aβ plaque load and the severity of neurofibrillary pathology or neuronal loss (8). In vivo and in vitro evidence suggests that soluble oligomeric forms of Aβ are the major toxic species in AD 9, 26, 46, 49.

Age is the most significant non‐genetic risk factor for AD. Levels of insoluble Aβ have been shown to increase with age in the human brain. Levels of formic acid‐extractable (ie, insoluble) Aβ1‐40 and Aβ1‐42 in the temporal and frontal cortex from human non‐demented controls were found to be positively associated with age between 18 and 92 years (13). In contrast, we recently found that levels of total soluble Aβ and oligomeric Aβ1‐42 normally decline with age (52). In young adults, the concentrations of soluble and oligomeric Aβ are not only higher than in older controls but also than in patients with AD.

The protein expression and enzyme activity of BACE‐1, the rate limiting enzyme in the production of Aβ, is increased in established AD 12, 13, 19, 27, 51, correlates with (insoluble) Aβ plaque load (27) and rises with age (13). Less is known about the effects of age on the processes of Aβ removal. Experiments in human Tg2576 APP mice showed reduced NEP mRNA, but unchanged protein levels with age (2). In the Tg2576 mice, IDE mRNA level was also unchanged, but protein level and enzyme activity increased with age compared to non‐significant changes in wild‐type littermates (23). With age, NEP mRNA level also declined in APPswe/PSEN1 (A246E) mice, whereas IDE mRNA level was unchanged; again, NEP protein level did not change significantly, although a trend towards an increased level was observed, but IDE protein level increased significantly (54). NEP and IDE 6, 33, 44, 62 protein and mRNA were reduced in brain tissue from AD patients; however, on adjustment for neuronal loss and examination of tissue from patients with intermediate as well as later Braak tangle stages, NEP and IDE enzyme activity were shown to increase with severity of disease (34). Inverse correlations were reported between NEP protein level and insoluble Aβ, as well as between NEP protein level and age (18), but these findings have yet to be repeated and, as far as we are aware, no data have been published on age‐related changes in the enzyme activities of NEP and IDE in the human brain.

In the present study, we have examined the influence of age on several aspects of Aβ production and degradation in post‐mortem human brain tissue. In particular, we have measured BACE‐1 activity, as well as the levels and activities of three putative Aβ‐degrading enzymes—neprilysin (NEP), insulin‐degrading enzyme (IDE) and angiotensin‐converting enzyme (ACE)—in normal controls ranging from 16 to 95 years in age. We have also compared these measurements to those in AD and looked at their relationships to the concentrations of total soluble, oligomeric Aβ1‐42 and total guanidine‐extractable (insoluble) Aβ.

MATERIALS AND METHODS

Study cohort

Brain tissue was obtained from the South West Dementia Brain Bank, University of Bristol, UK, and from the MRC Sudden Death Brain and Tissue Bank, Edinburgh University, UK. The study had Research Ethics Committee approval. All cases had been subjected to detailed neuropathological examination, which included immunohistochemistry for Aβ and phospho‐tau. The probability of AD had been assessed according to the criteria of the Consortium to establish a Registry for Alzheimer's disease (CERAD) (40).

The AD cohort (n = 84) included cases of both “definite” AD and “probable” AD. The AD cases ranged from 54 years to 98 years in age (mean = 79.5, SD = 9.0) and comprised 53 females and 31 males. The post‐mortem delays were between 4 h and 99 h (mean = 44.3, SD = 24.3). All had had a clinical diagnosis of dementia made during life by experienced clinicians with an interest in dementia and all had had a Mini‐Mental State Examination score of <17 (usually well below this) on several occasions prior to death. The controls (n = 68), with no history of cognitive decline or dementia, showing the absence of AD (as defined by CERAD) or other neuropathological abnormalities, and of Braak tangle stages 0–III, comprised 21 females and 47 males of ages ranging from 16 years to 95 years (mean = 60.6, SD = 23.5). Their post‐mortem delays were between 3 h and 115 h (mean = 48.8, SD = 28.1). For some analyses, the non‐AD controls were stratified according to age‐at‐death into three groups: younger (<40 years) and intermediate age (40–60 years) groups, and an older control group that was approximately matched in age (mean = 78.5, SD = 7.5) to the AD group. Total soluble, oligomeric Aβ1‐42 and total guanidine‐extracted Aβ levels had previously been measured in all cases (52). NEP, IDE and ACE protein levels and enzyme activities had previously been measured for the AD and older control groups 31, 32, 34, but not in the younger and intermediate‐age controls. All measurements of β‐secretase, Aβ‐degrading enzymes and Aβ levels were made on homogenates of mid‐frontal neocortex (Brodmann area 6).

Measurement of total soluble, oligomeric Aβ1‐42 and insoluble Aβ

The development and validation of the oligomeric Aβ1‐42 enzyme‐linked immunosorbent assay (ELISA), and measurement of oligomeric Aβ1‐42 by sandwich ELISA using a rabbit polyclonal Aβ1‐42 antibody (Millipore, Watford, UK) for the capture step and monoclonal mouse anti‐oligomeric Aβ antibody (clone 7A1a, New England Rare Reagents, Gorham, ME, USA) for the detection step, were reported previously 52, 53. The measurement of total soluble and insoluble Aβ in the cases in this study was also reported previously (52). Soluble and guanidine‐HCl extracted (insoluble) fractions were analysed by sandwich ELISA, in which monoclonal anti‐Aβ (4G8 clone, raised against amino acids 18–22; Millipore, Watford, UK) was used for the capture step and biotinylated anti‐human β‐amyloid monoclonal antibody (10H3 clone) (Thermo Fisher Scientific, Northumberland, UK) for the detection step.

Measurement of BACE‐1 activity

The β‐secretase‐specific fluorogenic substrate (Mca‐SEVNLDAEFRK(Dnp)RR‐NH2) containing the Swedish mutation of the APP BACE‐1 cleavage site (R&D systems) was used according to the manufacturer's guidelines to measure BACE‐1 activity in brain homogenates. 50 µl homogenates at 0.01 (wt/vol) dilution in 0.1 M sodium acetate (pH 4.0) (Sigma Aldrich, Gillingham, UK) were incubated with 20 µM fluorogenic substrate for 3 h at 37°C in a black F16 Nunc Maxisorp plate (Fisher Scientific, Loughborough, UK) in the dark. Fluorescence was measured with excitation at 320 nm and emission at 405 nm in a fluorescent plate reader (FLUOstar Optima, BMG Labtech, Aylesbury, UK). Each homogenate was assayed in duplicate in the presence and absence of a β‐secretase‐specific inhibitor (5 µM) (R & D systems). BACE‐1 activity was interpolated from a standard curve generated from serial dilutions of recombinant human BACE‐1 after subtraction of the inhibited from the uninhibited value. BACE‐1 activity was finally adjusted according to total protein content (measured using the TP0300 Total Protein Kit, Sigma Aldrich, according to the manufacturer's guidelines).

Measurement of NEP, IDE and ACE protein levels

NEP, IDE and ACE protein levels were determined by indirect sandwich ELISA, as previously described 31, 34. NEP and ACE were measured using the Neprilysin Duoset ELISA kit (R&D systems) and the ACE Duoset ELISA kit (R&D systems) according to the manufacturers' instructions. For measurement of IDE, we used an indirect sandwich ELISA with rabbit anti‐human IDE (inactive domain) capture antibody (Abcam, Cambridge, UK) and mouse anti‐IDE detection antibody (R&D Systems, Abingdon, UK) (34).

NEP and IDE activity assays

We used immunocapture‐based assays specific for NEP (37) and IDE (35) enzyme activity, as previously described (34). A NEP‐specific capture antibody (goat anti‐human NEP, R&D Systems) was used to isolate NEP from brain tissue homogenates prior to incubation with the fluorogenic peptide substrate Mca‐RPPGFSAFK‐OH (R&D Systems). The IDE activity assay used a rabbit polyclonal anti‐IDE (inactive domain) (Abcam) and the same fluorogenic peptide Mca‐RPPGFSAFK‐OH. The specificity and sensitivity of the assays were demonstrated in the earlier studies.

ACE‐1 activity assay

ACE‐1 activity was measured using the ACE‐1‐specific fluorogenic substrate Abz‐FRK(Dnp)‐P) (Biomol International, Exeter, UK) in the presence of captopril (1 mM), as detailed in Miners et al (32).

Statistical analysis

Data were analyzed by independent‐samples t‐test, one‐way ANOVA with Bonferroni post‐testing and Spearman's or Pearson correlation analysis, as appropriate, with the help of Statistical Package for Social Science software (12.0.1). Values of P < 0.05 were considered to be statistically significant. Inspection of the ELISA measurements of oligomeric Aβ1‐42 and total insoluble Aβ showed that the distributions were skewed to the right. These data were normalized by logarithmic transformation.

RESULTS

Age‐related changes in BACE‐1 and Aβ‐degrading enzyme activities

Increase in BACE‐1 activity with age

BACE‐1 activity was significantly higher in AD than age‐matched control brains (ie, the >60 years control group) (P = 0.0051) (Figure 1A). Among the combined controls (16 years–95 years), BACE‐1 activity correlated closely with age (r = 0.75, P < 0.0001) (Figure 1B). BACE‐1 activity differed significantly between the <40 years, 40 years–60 years and >60 years groups (P < 0.001). However, the activity was only slightly greater in the 40 years–60 years group than the <40 years and post hoc comparisons showed only the differences between these two groups and the >60 years group to be significant (P < 0.0001 for both comparisons) (Figure 1C).

Figure 1.

Figure 1

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β‐secretase activity increases with age in the normal brain and is further elevated in AD. (A) β‐secretase activity was significantly higher in AD than in age‐matched (>60 years) controls (P = 0.0051). The error bars indicate the standard error of the mean. (B) β‐secretase activity correlated with age (r = 0.75, P < 0.0001) in the combined control cohort. Each solid circle indicates the mean measurement in a single brain. The solid line shows the best‐fit linear regression line and the interrupted lines indicate the 95% confidence intervals. (C) β‐secretase actvity was significantly higher in the >60 years than the 40 years (P < 0.0001) and the 40 years–60 years (P < 0.0001) controls.

Increase in NEP and IDE activity, but not protein, with age

NEP protein level did not differ significantly between the three control groups (Figure 2A) and did not correlate with age in the combined control cohort (Figure 2B). In contrast, NEP activity was significantly different between the control cohorts (P < 0.0001, ANOVA) (Figure 2C). Post‐testing revealed significantly higher activity in the >60 years cohort than the <40 years (P < 0.001) or 40 years–60 years cohort (P < 0.05) (Figure 2C). NEP enzyme activity correlated with age in the combined control cohort (r = 0.528, P < 0.0001) (Figure 2D).

Figure 2.

Figure 2

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NEP enzyme activity increases with age in the normal brain. (A) NEP protein level did not differ between the <40 years, 40 years–60 years and >60 years control cohorts and (B) did not correlate with age. (C) NEP activity was significantly greater in the >60 years cohort than the <40 years (P < 0.001) and 40 years–60 years (P < 0.05) control cohorts and (D) showed significant correlation with age in the controls (r = 0.528, P < 0.0001).

IDE protein level did not differ significantly between the three control groups (Figure 3A) and was not associated with age in the combined control cohort (Figure 3B). IDE enzyme activity differed significantly between the control groups (P < 0.0001, ANOVA) (Figure 3C) with significantly higher activity in the >60 years cohort than in either of the other control cohorts (P = 0.001 for both comparisons) (Figure 3D). IDE activity correlated with age in the combined control cohort (r = 0.463, P < 0.0001) (Figure 3D).

Figure 3.

Figure 3

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IDE enzyme activity increases with age in the normal brain. (A) IDE protein level did not differ between the <40 years, 40 years–60 years and >60 years control cohorts and (B) did not correlate with age. (C) IDE activity was significantly increased in the >60 years cohort compared to both the <40 years (P = 0.001) and the 40 years–60 years (P = 0.001) control cohorts and (D) correlated with age in the combined controls (r = 0.43, P < 0.0001).

No change in ACE activity with age

ACE protein level did not vary significantly between the three control groups (Figure 4A). A trend toward a positive association between ACE protein and age was observed in the combined control cohort, but this did not reach significance (r = 0.19, P = 0.087) (Figure 4B). Likewise, ACE enzyme activity did not differ significantly between control cohorts (Figure 4C) and was not associated with age (Figure 4D) (but was significantly increased in AD, as previously reported (31)).

Figure 4.

Figure 4

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ACE protein and enzyme activities do not change with age in the normal brain. ACE protein (A, B) and enzyme activity (C, D) did not differ significantly between the <40 years, 40 years–60 years and >60 years control cohorts and did not correlate with age.

Relationships between BACE‐1 and Aβ‐degrading enzyme activities and Aβ

BACE‐1 activity correlates with total insoluble Aβ, and inversely with total soluble and oligomeric Aβ1‐42

In the control cohort, BACE‐1 activity correlated directly with total insoluble Aβ (r = 0.313, P = 0.018) (Table S1), but inversely with total soluble Aβ (r = −0.488, P = 0.001) and oligomeric Aβ1‐42 (r = −0.433, P < 0.0001). BACE‐1 activity did not correlate with Aβ levels in the AD cohort.

BACE‐1 activity correlates with Aβ‐degrading enzyme activity

NEP activity correlated with BACE‐1 activity in both controls and AD (r = 0.471, P < 0.0001 in controls; r = 0.222, P = 0.038 in AD) (Table S2). No correlation was observed between BACE‐1 activity and NEP protein level. IDE activity also correlated with BACE‐1 activity in controls (r = 0.570, P < 0.0001), but not AD (Table S2). IDE protein level did not correlate with BACE‐1 activity. There was a correlation between ACE activity and BACE‐1 activities in controls (r = 0.376, P = 0.001), but not AD. Conversely, ACE protein level correlated with BACE‐1 activity in the AD cohort (r = 0.220, P = 0.040), but not the controls.

Correlations with soluble, oligomeric Aβ and insoluble Aβ differ for Aβ‐degrading enzyme levels and activities

NEP activity was inversely related to total soluble Aβ in controls (r = −0.393, P = 0.003) and AD (r = −0.226, P = 0.048) (Table S3). Oligomeric Aβ1‐42 was inversely related to NEP activity in controls (r = −0.318, P = 0.012) (Table S3) but not AD. IDE activity correlated directly with insoluble Aβ (r = 0.385, P = 0.003) (Table S3) in the control cohort only. Neither NEP nor IDE protein level correlated with Aβ measurements.

ACE activity did not correlate with Aβ measurements in the control or AD cohorts. However, ACE protein level did correlate directly with insoluble Aβ (r = 0.421, P = 0.001) (Table S3) and inversely with soluble Aβ (r = −0.268, P = 0.046) in the controls.

Aβ‐degrading enzyme (NEP, IDE and ACE) and BACE‐1 are not affected by post‐mortem delay or gender

No gender‐specific difference was observed for BACE‐1 activity or for NEP, IDE or ACE protein level or enzyme activity. No significant correlation was found between BACE‐1, NEP, IDE or ACE level or activity and post‐mortem interval (data not shown).

DISCUSSION

We previously showed that soluble Aβ, oligomeric Aβ1‐42 and guanidine extractable (insoluble) Aβ levels were increased in AD compared to age‐matched controls (52). However, soluble levels (including oligomeric forms of Aβ1‐42) were higher still in younger adults and, in the absence of AD, declined with age. In keeping with other studies the level of insoluble Aβ, particularly insoluble Aβ1‐42, is increased with age (13). Our present findings reveal that the activities of NEP, IDE and BACE‐1 all increase with normal ageing, although not as much as in AD. BACE‐1 activity correlated directly with those of NEP, IDE and ACE. BACE‐1, IDE and ACE activities also correlated directly with insoluble Aβ level, and BACE‐1 activity and ACE protein level inversely with soluble Aβ level.

Our finding that BACE‐1 activity is higher in AD than in age‐matched controls agrees with several previous reports 12, 19, 27, 51, as does the correlation between BACE‐1 activity and insoluble Aβ load 13, 27. An age‐related increase in BACE‐1 activity has also been observed in APP transgenic mice and primates as well as in human post‐mortem brain tissue (13). The inverse relationship between BACE‐1 activity and the levels of soluble and oligomeric Aβ has not previously been documented and raises the possibility that BACE‐1 is up‐regulated by a fall in the concentration of soluble Aβ. Alternatively, as suggested by Zhao et al (61), BACE‐1 may be up‐regulated by insoluble Aβ. The striking increase in BACE‐1 activity in older adults compared with younger control cohorts is in keeping with previous suggestions 13, 19, 27, 51 of a role for elevated BACE‐1 activity in mediating some of the risk of increasing age in the development of late‐onset sporadic AD.

Although some early studies, including our own, found reductions in NEP 1, 36, 55, 60 and IDE protein or mRNA levels in AD 33, 44, 62, examination of the specific enzyme activities in large cohorts before and after adjustment for neuronal loss revealed that the enzyme activities of NEP and IDE are elevated in AD and increase with progression of disease (as indicated by Braak tangle stage) (34). We also found that ACE activity is increased in AD (31). The present findings indicate that the activities of NEP and IDE but not ACE increase with age and are considerably lower in younger adults without neurological disease than in patients with AD. These data do not support a role for declining Aβ‐degradation with age as a cause of AD.

In human APP (Tg2576) 2, 23 and APPswe/PSEN1 (54) transgenic mice, NEP mRNA level was reduced, whereas NEP protein level remained unchanged with age. In these same models, IDE mRNA level was unchanged but protein and enzyme activity levels increased with age. The increase in IDE coincided with accumulation of insoluble Aβ(23). Both NEP (2) and IDE (23) were demonstrated immunohistochemically in reactive astrocytes adjacent to Aβ plaques. The authors suggested that local Aβ‐related inflammation was responsible for inducing NEP and IDE expression within the astrocytes. The same suggestion was made by Vepsalainen et al (54), who showed that NEP and IDE protein levels were higher in APPswe/PSEN1 transgenic mice than non‐transgenic littermates. Furthermore, dose‐dependent induction of neuronal NEP expression has been demonstrated in human APP transgenic mice (APPswe) following injection of synthetic fibrillar Aβ38, 39. In vitro, fibrillar but not soluble Aβ up‐regulated NEP (57), ACE (31) and IDE (23), as well as other potential Aβ‐degrading enzymes such as MMP‐2 (20) and ‐9 (25). In two strains of mouse transgenic for mutant human APP, BACE‐1 protein level (but not BACE1 mRNA) rose only after accumulation of plaque‐associated Aβ, although the timing of plaque formation differed widely between the two strains (61). The authors concluded that Aβ deposition caused elevation in BACE‐1 protein through a post‐transcriptional mechanism, driving a deleterious positive‐feedback loop in AD. These data raise the possibility that fibrillar Aβ may induce up‐regulation of Aβ‐degrading enzymes to protect against further Aβ accumulation caused in part by increased BACE‐1 activity.

NEP expression was shown to be induced by APP intracellular domain (AICD) 42, 43 which is co‐generated with Aβ during γ‐secretase‐mediated cleavage of APP. Gleevec, a tyrosine kinase inhibitor, increased NEP mRNA and protein in vitro in association with increased AICD levels (11). Other researchers did not find evidence that APP processing influenced expression of NEP 5, 17, 41. However, a recent study demonstrated that AICD bound directly to the NEP promoter in human neuroblastoma (NB7) cells (3), providing further evidence that AICD may play a role in controlling the expression of NEP.

Our data highlight the importance of measuring the activity rather than solely the protein levels of enzymes involved in the synthesis and degradation of Aβ. The dissociation between enzyme protein levels and activities is in line with data from animal studies and suggests that Aβ may cause post‐translational modification of NEP and IDE. Some of the effects of Aβ are probably indirectly mediated, for example, through inflammatory processes. The induction of IDE activity in astrocytes (from Tg2576 mice) exposed to fibrillar Aβ was inhibited by UO126 (23), an inhibitor of the ERK1/2 mitogen‐activated protein kinase cascade, which is activated by a range of growth factors and cytokines. At present, little is known about post‐translational modifications of NEP and IDE. NEP undergoes post‐translational modification by N‐glycosylation, and has also shown to be phosphorylated by casein kinase 2 in vitro (14). However, the phosphorylation state of NEP and the biological relevance of phosphorylation remain to be determined.

The conformation of Aβ peptide influences both amyloid formation and resistance to proteolysis 7, 47, which is one reason why accumulation of fibrillar Aβ tends to be progressive. Fibrillar assembly of Aβ is enhanced by increased concentration of the peptide and by some Aβ mutations (4), but is also modulated by a range of microenvironmental factors (reviewed in (29)). These include the relative concentrations of metals (and their ions). For example, the level of zinc is increased in AD (45), which may promote Aβ fibril formation. It is not known whether zinc levels increase in the brain during normal aging. Some authors have argued that the formation of aggregates of insoluble Aβ is protective rather than harmful (24). Aβ plaques may, for example, seed the removal of toxic oligomers from the interstitial fluid. This would be in keeping with the inverse relationship between soluble and insoluble forms of Aβ in human post‐mortem brain tissue (52) as well as Tg2576 mice (21).

In conclusion, we have shown an increase with age in the activities of both Aβ‐synthesizing and ‐degrading enzymes that seems to be mediated by post‐translational modification and coincides with a decline in the concentration of soluble (including oligomeric) forms of Aβ and a progressive increase in insoluble Aβ. We suggest that establishing whether these changes in enzyme activity and Aβ levels are causally related, and if so how, are critical to obtaining a better understanding of the pathogenesis of late‐onset sporadic AD.

Supporting information

Table S1. Correlation between BACE‐1 activity and Aβ.

Table S2. Correlation between BACE‐1 activity and Aβ‐degrading enzymes.

Table S3. Correlation between Aβ‐degrading enzymes and Aβ.

Please note: Wiley‐Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

Supporting info item

Click here for additional data file. (43.5KB, doc)

ACKNOWLEDGMENTS

This work was supported by Alzheimer's Research Trust. We are grateful to the MRC Sudden Death Brain and Tissue Bank, University of Edinburgh, UK, for providing tissue.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1. Correlation between BACE‐1 activity and Aβ.

Table S2. Correlation between BACE‐1 activity and Aβ‐degrading enzymes.

Table S3. Correlation between Aβ‐degrading enzymes and Aβ.

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