| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Department of Neurology,* Alzheimer Disease Research Unit, Massachusetts General Hospital–East, Charlestown, Massachusetts; Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts; and the Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
-secretase complex that releases the C-terminus of Aß from the membrane. The increased levels of Aß in most autosomal-dominant inherited forms of familial AD are attributed to mutations in presenilin or APP.9,10
In the majority of sporadic AD cases, without these mutations, increased levels may be because of increased production11-13
or reduced catabolism14
of Aß. However, levels of APP substrate or -secretase components do not seem to increase with age: APP expression is uniform with aging, and presenilin mRNA levels are actually highest in the embryonic brain, and then markedly decline to remain stable with increasing age.15,16 Tg2576 transgenic mice, which express mutant human APP (KM670-1NL) under the hamster prion protein promoter, develop cortical and limbic amyloid deposits only with aging;4 cognitive deficits occur coincident with increasing Aß levels.17 Similar to the case in human aging and sporadic AD, increased levels of mouse Aß with age are not associated with increased levels of APP or presenilin.15,18-20
Nonhuman primates have also served as models of age-associated neuropathological changes and cognitive impairment. Aß deposition occurs in the brains of aged nonhuman primates,6,7,21 although Aß deposition in monkeys does not correlate with cognitive decline.7 Age-related alterations in the subcellular distribution of presenilin have been reported in cynomolgus monkey brain.22
Although the level of BACE mRNA also does not appear to be altered in AD or transgenic mouse models of AD,20,23 BACE enzymatic activity is elevated in AD brain, particularly in cortical regions susceptible to degeneration.11-13 Interestingly, BACE activity seems to increase out of proportion to BACE protein levels in AD temporal cortex.12
We tested the hypothesis that the accumulation of Aß in the aging brain is associated with an age-related increase of BACE enzymatic activity. We studied BACE protein, BACE activity, and Aß protein levels in the postmortem brains of a wide age-range of APP transgenic and nontransgenic mice (line Tg2576), rhesus monkeys, and humans.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
In the Tg2576 mouse line, the human APP695 KM670-1NL transgene was expressed under the hamster prion protein promoter in C57B6/SJL F1 mice backcrossed to C57B6/SJL breeders.4 Age-matched nontransgenic littermates served as controls.
To determine the effects of aging and transgene status on BACE protein and activity, male Tg2576 transgenic mice (young at 4 months, n = 8; aged at 14 to 18 months, n = 9) and nontransgenic littermates (young at 4 months, n = 9; aged at 14 to 18 months, n = 7) were studied. The right hemisphere was dissected for BACE assays and the left for Aß determination.
Monkey Brain
We analyzed archived fresh-frozen frontal and temporal cortex from a cohort of young (4.4 to 12.7 years) and old (20.9 to 30.4 years) rhesus monkeys. All monkeys were carefully screened to exclude any with a history of experimental manipulation or disease that could affect the brain, and they were part of an ongoing study of aging in monkeys.7 The samples were of the frontal cortex of 6 young and 11 old rhesus monkeys and the temporal cortex of 4 young and 7 old rhesus monkeys. All samples were flash-frozen with a postmortem interval of 20 minutes or less and stored at -80°C until processed.
Human Brain
Frozen temporal cortex slices [Brodman Area (BA) 20, 21, 22], frontal association cortex (BA 9, 10), and cerebellum were obtained from control brains in the Massachusetts Alzheimer Disease Research Center brain bank (n = 2), the Harvard Brain Tissue Resource Center (n = 5). and the University of Maryland Developmental Brain and Tissue Bank for Developmental Disorders (n = 18). Control brains had no history of dementia ante-mortem and did not satisfy National Institute of Aging and the Reagan Institute Working Group pathological criteria for AD,24 although three brains had diffuse cortical amyloid deposits without cortical neurofibrillary tangles. The cases ranged in age from 18 to 92 years (average ± SD, 46.5 ± 21.1 years), with postmortem intervals of 4 to 26 hours (13.6 ± 5.8 hours).
Tissue Processing
For the BACE protein enzyme-linked immunosorbent assay (ELISA) and BACE activity assay, frozen tissues were homogenized with a mechanical homogenizer in 10 µl/mg (volume per wet weight) of Tris buffer (Tris 50 mmol/L, pH 7.4, 400 mmol/L NaCl, 2 mmol/L ethylenediaminetetraacetic acid) containing 0.1% Triton X-100, protease inhibitors (Complete; Roche, Indianapolis, IN) and 2% protease-free bovine serum albumin. The soluble fraction was extracted after centrifugation at 15,000 rpm for 5 minutes at 4°C. For the formic acid-extractable Aß ELISA, each tissue was homogenized in Tris buffer with 0.1% Triton X-100 (human, monkey) or without Triton X-100 (mouse), with protease inhibitors and 2% bovine serum albumin. The homogenate was centrifuged at 15,000 rpm for 5 minutes at 4°C. The resulting pellet was homogenized in 70% formic acid then recentrifuged at 22,000 rpm for 5 minutes at 4°C. The supernatant was neutralized with 1 mol/L Tris buffer, pH 11, and used for assay of formic acid-extractable Aß.
BACE Activity Assay
Black plates (MaxiSorp; Nunc, Rochester, NY) were coated with MAB5308 (monoclonal mouse anti-BACE C-terminus; Chemicon, Temecula, CA) 1:4000 in carbonate buffer, pH 9.6, overnight at 4°C, then washed three times with phosphate-buffered saline (PBS), and blocked with BlockAce (25% in PBS; Dai-Nippon, Osaka, Japan) for more than 6 hours at 4°C. After three washes with PBS, samples (50 µl of 0.01 or 0.005 dilution, wet weight in mg to volume of homogenization buffer in µl) were added to each well containing Superblock (50 µl; Pierce, Rockford, IL). Plates were incubated for 1 hour at 37°C and then washed six times with PBS. The enzymatic reaction was performed by incubation with 10 µmol/L of fluorescent quenching substrate for BACE [H-RE(EDANS)EVNLD-AEFK(DABCYL)R-OH (ß-secretase substrate IV; Calbiochem, San Diego, CA)] in acetate buffer/100 mmol/L NaCl (pH 4.1) containing 0.025% bovine serum albumin for 16 to 24 hours at 37°C. The enzymatic product was measured on a Wallac Victor V2 plate reader (Perkin-Elmer, Wellesley, MA) using a 355-nm excitation filter and a 510-nm emission filter. Serial dilutions of the same temporal cortex homogenate were used as the standard for each plate. The operating characteristics of the BACE activity assay have been published.12
ELISAs
The BACE protein ELISA used capture antibody MAB5308 and detector antibody PA1-756 (polyclonal rabbit anti-BACE N-terminus; Affinity Bioreagents, Golden, CO), as detailed in Fukumoto and colleagues.12 We developed a new ELISA specific for pro-BACE. Pro-BACE protein ELISA was performed under the same conditions using capture antibody MAB5308 and a rabbit polyclonal detector antibody directed against amino acid residues 26 to 45, specific for the prodomain of BACE (Calbiochem). Aß ELISAs were performed with BNT77 (monoclonal anti-Aß11-28; Takeda, Osaka, Japan) as the capture and horseradish peroxidase-conjugated BA27 (monoclonal anti-Aß40, Takeda) or BC05 (monoclonal anti-Aß42, Takeda) as the detector antibodies, using human Aß40 and Aß42 as standards (Bachem, King of Prussia, PA).12,25
Western Blot
To evaluate gross changes in migration pattern and processing of BACE in the aging cohort, we performed Western blot of the brain homogenates of human aging brain and monkey brain. Homogenates were performed as above in Triton buffer without bovine serum albumin, and protein measured by Bio-Rad Protein Assay (Hercules, CA). Protein (20 to 40 µg) was run on 10 to 20% and 8% Tris-glycine gels (Invitrogen, Carlsbad, CA) under denaturing and reducing conditions and transferred to Immobilon polyvinylidene difluoride membrane at 22 V overnight at 5°C. The membrane was blocked with 5% nonfat dry milk in TBS-T and sequentially probed with primary antibody (mouse anti-BACE C-terminus MAB5308, 1:1000 or rabbit anti-BACE 26-45, 1:1000) and secondary antibody (horseradish peroxidase anti-mouse or anti-rabbit IgG, 1:2000; Jackson, West Grove, PA). Protein binding was visualized by enhanced chemiluminescence (Perkin-Elmer) on X-ray film (Kodak, Rochester, NY), scanned by densitometer (PowerLook III; UMAX, Dallas, TX), with relative optical density quantitated using Molecular Analyst Software (Bio-Rad).
Statistical Analysis
For the mouse and monkey studies, analysis of variance was performed with BACE or Aß measures as the dependent variables and age (young versus aged) and brain region as the independent variables. For human studies, with a range of ages, correlation analysis between age, BACE, and Aß measures were performed for each brain region (StatView; Abacus Concepts, Berkeley, CA).
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Consistent with previous studies of pathological measures in the aging brain, we found that biochemical measures of formic acid-extractable Aß increased with aging in all cohorts studied (Figure 1)
. In nontransgenic mice, Aß increased with age [F(1,26) = 18.2, P = 0.0002], by fourfold in the cerebral cortex [t(13) = 2.9, P = 0.01] and 14-fold in the cerebellum [t(13) = 3.8, P = 0.002] (Figure 1A)
. Aß measures were several orders of magnitude greater in the APP transgenic mice, increasing to an even greater extent with age [F(1,30) = 34.8, P < 0.0001], reflecting a 155-fold increase in the cerebral cortex [t(15) = 5.6, P < 0.0001] and a 37-fold increase in the cerebellum [t(15) = 5.3, P < 0.0001] between the ages of 4 months and 14 to 18 months (Figure 1B)
.
|
.
In humans, formic acid-extractable Aß increased exponentially with age in temporal and frontal cortex but not cerebellum (Figure 1
; D to F). There were significant correlations between the log of formic acid Aß levels with age in the neocortical regions (Figure 1
; D to E), reflecting significant age-related increases in temporal Aß40 [r2(25) = 0.34, P = 0.002] and Aß42 [r2(25) = 0.48, P = 0.0001] (Figure 1D)
as well as frontal Aß40 [r2(23) = 0.27, P = 0.01] and Aß42 [r2(23) = 0.47, P = 0.0002; Figure 1E
].
BACE Activity Increases in the Brain with Aging
BACE activity is increased in AD neocortex.11-13 Because the primary risk factor for AD is aging,1 we investigated BACE activity in aging human brain, in transgenic mouse models of AD, in which amyloid deposits also only occur with increasing age,18,19 as well as in rhesus monkeys that develop diffuse amyloid deposits with aging.6,26,27 The study of nontransgenic mouse littermates further allowed us to determine whether BACE activity was altered by overexpression of its substrate, APP, in the transgenic mice.
BACE activity increased with age in both nontransgenic [F(1,28) = 21.1, P < 0.0001] and transgenic mice [F(1,30) = 58.8, P < 0.0001; Figure 2, A and B
]; however, amyloid plaques only form in the transgenic mice, which express high levels of the mutant human APP substrate susceptible to ß-secretase cleavage.19
In transgenic mice, BACE activity increased by 21% in cortex [t(15) = 5.4, P < 0.0001], an area susceptible to Aß deposition in APP transgenic mice, and by 66% in cerebellum [t(15) = 5.9, P < 0.0001], an area usually spared of amyloid deposits except as amyloid angiopathy (Figure 2B)
. There were similar changes in the nontransgenic mice, in which BACE activity increased by 16% in cortex [t(14) = 3.5, P = 0.004] and 63% in cerebellum [t(14) = 3.6, P = 0.003; Figure 2A
]. BACE activity levels did not differ by genotype (transgenic versus nontransgenic) at either age.
|
].
In human brain samples, age was significantly associated with increasing BACE activity in temporal [r2(25) = 0.29, P = 0.005], frontal [r2(22) = 0.34, P = 0.004], and cerebellar cortex [r2(25) = 0.21, P = 0.02; Figure 2
; D to F]. There was no association of BACE activity levels with postmortem interval in the range of 4 to 26 hours in any of the brain regions evaluated (r2 < 0.09, P > 0.28).
There Are No Significant Changes in Brain BACE Protein Levels with Aging
To determine whether the age-related increase in BACE enzymatic activity was because of elevation in BACE protein levels with age, BACE protein levels were determined in the brain specimens by ELISA. BACE protein levels were not affected by aging in nontransgenic mice [F(1,28) = 1.8, P = 0.19; Figure 3A
], Tg2576 APP transgenic mice [F(1,30) = 2.0, P = 0.17; Figure 3B
], rhesus monkey [F(1,24) = 0.65, P = 0.43; Figure 3C
], or human brain regions (r2 < 0.15, P > 0.05; Figure 3
; D to F). There was no association of BACE protein levels with postmortem interval in any of the brain regions studied (r2 < 0.01, P > 0.80). ELISA specific for the proprotein form of BACE did not show any association of pro-BACE levels with aging in humans (r2 < 0.11, P > 0.11). Pro-BACE levels correlated with BACE levels in human temporal cortex [r2(25) = 0.49, P = 0.0001] and human cerebellum [r2(25) = 0.44, P = 0.0003], but not frontal cortex [r2(23) = 0.05, P = 0.29].
|
, likely representing posttranslational modifications of BACE. Western blot with the pro-BACE antibody in the human samples demonstrated a doublet at 
64 kd and a weak broad band at 58 kd (Figure 4)
. There were no consistent changes in the pattern of bands with aging in human or monkey frontal or temporal cortex. Quantitation of the Western blot bands did not reveal any increase in BACE or pro-BACE protein with aging to account for the increased BACE activity in human or monkey frontal and temporal cortex.
|
Because BACE activity increased out of proportion to changes in BACE protein with aging in each cohort and in AD temporal cortex,12
we evaluated the ratio of BACE activity to BACE protein (BACE act/prt) for each case in the mouse, monkey, and human brain cohorts (Figure 5)
. The ratio increased in nontransgenic mouse brain [F(1,28) = 24.6, P < 0.0001] with a 41% increase in cortex [t(14) = 3.2, P = 0.006] and a 101% increase in cerebellum [t(14) = 3.8, P = 0.002; Figure 5A
]. Comparable increases with aging were seen in the transgenic mouse brains [F(1,30) = 21.6, P < 0.0001] with a 62% increase in cortex [t(15) = 3.1, P = 0.008] and a 116% increase in cerebellum [t(15) = 3.9, P = 0.001; Figure 5B
].
|
.
In the human cohort, BACE act/prt increased with aging in temporal cortex [r2(25) = 0.48, P = 0.0001], frontal cortex [r2(22) = 0.46, P = 0.0005], and cerebellum [r2(25) = 0.44, P = 0.0003; Figure 5
; D to F]. These data and the Western blot data suggest that the changes in BACE activity levels with aging are not simply because of changes in BACE protein levels, and that age-related posttranslational changes or allosteric modulation of BACE activity occur.
BACE Activity Correlates Inconsistently with Formic Acid-Extractable Aß in the Brain
Because BACE is the initial enzyme in Aß synthesis, we investigated whether BACE activity correlated with insoluble Aß measures. In both transgenic and nontransgenic mice, total formic acid-extractable Aß increased exponentially relative to BACE activity, and correlations were performed relative to the log total formic acid Aß level. Significant correlations were found in nontransgenic cortex [r2(15) = 0.41, P = 0.01] and cerebellum [r2(15) = 0.59, P = 0.0008] as well as in transgenic cortex [r2(17) = 0.60, P = 0.0002] and cerebellum [r2(17) = 0.78, P < 0.0001; Figure 6, A and B
]. In the monkey brains, there were no significant associations between formic acid-extractable Aß measures and BACE activity (Figure 6C)
. In human brain, formic acid-extractable Aß levels increased exponentially relative to BACE activity levels in neocortex, with weak associations between BACE activity and log Aß measures for temporal cortex Aß40 [r2(25) = 0.17, P = 0.04], frontal cortex Aß40 [r2(22) = 0.28, P = 0.01], and frontal cortex Aß42 [r2(22) = 0.44, P = 0.0008; Figure 6
; D to F].
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
BACE is a pivotal enzyme for the initial cleavage of full-length APP to generate the ß-secretase cleavage fragment APPß, which is subsequently cleaved by -secretase to generate Aß. We find that levels of BACE activity increase with aging in each of the species studied, potentially contributing to increased synthesis of Aß by BACE. We postulate that the elevation of BACE activity (up to twofold in the human neocortex) may be sufficient throughout time to alter the balance of Aß generation and clearance, leading to Aß oligomerization, fibrillization, and ultimately deposition as senile plaques in AD.
There are only weak associations of BACE activity with Aß levels, which are variable across species. The strongest associations are in the mice, consistent with findings demonstrating increased levels of Aß with BACE overexpression,29 and elimination of Aß with BACE knockout in mice.30,31 However, other factors affect Aß levels in brain. The absolute Aß levels that we measured reflect the sum of multiple complex processes including Aß production, oligomerization, fibrillization, deposition, uptake, clearance, and degradation. We anticipate that these processes vary in different brain regions, leading to the observed pattern of Aß deposition in neocortex with relative sparing of the cerebellum (despite Aß generation in all brain regions.) For example, chaperone proteins (apolipoprotein E, apolipoprotein J), Aß receptors (receptor for advanced glycation end-products, RAGE; macrophage scavenger receptor, MSR; low-density lipoprotein receptor related protein, LRP), proteolytic enzymes (neprilysin, endothelin converting enzyme, and insulin degradation enzyme), and extracellular matrix composition, likely contribute to the absolute levels and regional distribution of Aß,32 modifying quantitative correlations of BACE activity with Aß across species.
The increased BACE activity associated with aging and AD is distinct from any changes in BACE protein or mRNA levels. BACE activity is optimal at pH 3.5 to 4.5,12,33 therefore sorting of BACE into acidic endosomal/lysosomal compartment may regulate BACE activity.34,35 Other factors, including endoproteolysis,36 oxidative stress,37 membrane cholesterol composition,38,39 interactions with nicastrin,40 phospholipid scramblase 1,39 and chronic inflammation41,42 have been reported to affect BACE expression or activity in neuronal and astrocytic cells. However, the activity assay we report measures BACE isolated from brain homogenates, so the age-related increases in BACE activity cannot be explained by changes in subcellular distribution and interactions alone.
This suggests that posttranslational modification, allosteric modulation, or co-factor association augments the enzymatic activity of BACE during aging. BACE is produced as an active proprotein with different enzyme kinetics relative to BACE.43,44 Splice variants of BACE possess reduced enzymatic activity.45 BACE also undergoes phosphorylation, glycosylation, and palmitoylation with unknown effects on enzymatic activity.34,46-48 The effects of aging on the relative distributions of these differentially active forms of BACE remains to be clarified. Although we could identify no gross changes in the pattern of BACE migration in aging human and monkey brains by Western blot, and no increases in total BACE and pro-BACE protein levels in aging human brain, more detailed proteomic analysis of BACE will prove critical for understanding these pathophysiological events. Because aging is the strongest risk factor for AD, and BACE activity increases with aging and to a greater extent in sporadic AD, AD may reflect an exaggeration of age-related changes in BACE activity. These data support BACE as a pharmacological target to prevent the age-associated increased synthesis of Aß that may serve as a harbinger of AD.
|
Footnotes |
|---|
Supported by the National Institutes of Health (AG15453 to B.T.H. and AG05134 to Massachusetts Alzheimer Disease Research Center; AG00001 to Boston University, RR00165 to Emory University, PHS MH/NS 31862 to Harvard Brain Tissue Resource Center); the University of Maryland Developmental Brain and Tissue Bank for Developmental Disorders; the American Federation for Aging Research Beeson Award (to M.C.I.); the Harvard University W.F. Milton Fund (to M.C.I.); the J.D. French Foundation, Los Angeles, CA (to M.C.I.); and Takeda Chemical Industries, Osaka, Japan (to H.F.).
Accepted for publication October 15, 2003.
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  X. Sun, G. He, H. Qing, W. Zhou, F. Dobie, F. Cai, M. Staufenbiel, L. E. Huang, and W. Song Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression PNAS, December 5, 2006; 103(49): 18727 - 18732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Sun, Y. Tong, H. Qing, C.-H. Chen, and W. Song Increased BACE1 maturation contributes to the pathogenesis of Alzheimer's disease in Down syndrome FASEB J, July 1, 2006; 20(9): 1361 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Sun, G. He, and W. Song BACE2, as a novel APP {theta}-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome FASEB J, July 1, 2006; 20(9): 1369 - 1376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Zhou and W. Song Leaky Scanning and Reinitiation Regulate BACE1 Gene Expression. Mol. Cell. Biol., May 1, 2006; 26(9): 3353 - 3364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kern, B. Roempp, K. Prager, J. Walter, and C. Behl Down-regulation of Endogenous Amyloid Precursor Protein Processing due to Cellular Aging J. Biol. Chem., February 3, 2006; 281(5): 2405 - 2413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, W. Zhou, Y. Tong, G. He, and W. Song Control of APP processing and A{beta} generation level by BACE1 enzymatic activity and transcription FASEB J, February 1, 2006; 20(2): 285 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sastre, I. Dewachter, S. Rossner, N. Bogdanovic, E. Rosen, P. Borghgraef, B. O. Evert, L. Dumitrescu-Ozimek, D. R. Thal, G. Landreth, et al. Nonsteroidal anti-inflammatory drugs repress {beta}-secretase gene promoter activity by the activation of PPAR{gamma} PNAS, January 10, 2006; 103(2): 443 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liang, Q. Wang, T. Hand, L. Wu, R. M. Breyer, T. J. Montine, and K. Andreasson Deletion of the Prostaglandin E2 EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease J. Neurosci., November 2, 2005; 25(44): 10180 - 10187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. H. Koh, C. A. F. von Arnim, B. T. Hyman, R. E. Tanzi, and G. Tesco BACE Is Degraded via the Lysosomal Pathway J. Biol. Chem., September 16, 2005; 280(37): 32499 - 32504. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Vandenberghe and J Tournoy Cognitive aging and Alzheimer's disease Postgrad. Med. J., June 1, 2005; 81(956): 343 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Lim, F. Calon, T. Morihara, F. Yang, B. Teter, O. Ubeda, N. Salem Jr, S. A. Frautschy, and G. M. Cole A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model J. Neurosci., March 23, 2005; 25(12): 3032 - 3040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. H. Gylys, J. A. Fein, F. Yang, D. J. Wiley, C. A. Miller, and G. M. Cole Synaptic Changes in Alzheimer's Disease: Increased Amyloid-{beta} and Gliosis in Surviving Terminals Is Accompanied by Decreased PSD-95 Fluorescence Am. J. Pathol., November 1, 2004; 165(5): 1809 - 1817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schmechel, M. Strauss, A. Schlicksupp, R. Pipkorn, C. Haass, T. A. Bayer, and G. Multhaup Human BACE Forms Dimers and Colocalizes with APP J. Biol. Chem., September 17, 2004; 279(38): 39710 - 39717. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
