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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:B16-B21 (2002)
© 2002 The Gerontological Society of America

Leukocyte Lysosomal Enzymes in Alzheimer's Disease and Down's Syndrome

Svjetlana Kalanj-Bognara, Tanja Rundekc,d, Ivana Furacb, Vida Demarinc and Cedomir Cosovica

a Departments of Chemistry and Biochemistry, School of Medicine, University of Zagreb, Croatia
b Departments of Forensic Medicine and Criminology, School of Medicine, University of Zagreb, Croatia
c University Department for Neurology, University Hospital "Sestre milosrdnice," Zagreb, Croatia
d Neurological Institute, New York Presbyterian Hospital at Columbia University, New York

Svjetlana Kalanj-Bognar, Department of Chemistry and Biochemistry, School of Medicine, University of Zagreb, ©alata 3, 10000 Zagreb, Croatia E-mail: Svjetla{at}mamef.mef.hr.

Decision Editor: John Faulkner, PhD


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
Previous studies suggested the possibility of accelerated lysosomal degradation of brain gangliosides in Alzheimer's disease (AD). As AD pathology affects both neural and nonneural tissues, the aim of this study was to determine possible changes of glycosphingolipid metabolism in available peripheral cells in AD and Down's syndrome (DS). The activities of several lysosomal enzymes involved in catabolism of gangliosides and sulfatides were measured in leukocytes from subjects with dementia of the Alzheimer type, DS, and age-matched controls, by fluorimetry and spectrophotometry using specific substrates. The results showed a statistically significant increase of ß-galactosidase activity in both dementia of the Alzheimer type and DS leukocytes when compared with age-matched controls (p < .01 and p < .05, respectively; Student's t test). Not significantly increased activities of ß-galactosidase, ß-hexosaminidase, ß-hexosaminidase A, and slightly decreased activity of arylsulfatase A were observed in control leukocytes with aging. Our results indicate that a metabolic dysfunction and the acceleration of at least some lysosomal catabolic pathways are present in AD and DS nonneural cells.

ALZHEIMER'S disease (AD) is a neurodegenerative disorder of unknown etiology. The hypothesis of disturbed glycosphingolipid (GSL) metabolism in AD is based on several facts. First, previous studies showed changes in content and composition of brain gangliosides in Alzheimer's disease (1), and they suggested the possibility of accelerated lysosomal degradation of GSLs in AD brains (2). Second, numerous studies have shown that pathologic processes and biochemical disturbances in AD affect not only neural but also nonneural tissues (3)(4)(5)(6)(7)(8)(9)(10). Third, the majority of biochemical disorders in neural and nonneural tissue result in seriously damaged structure, function, and fluidity of cell membranes (11)(12)(13)(14)(15). Finally, gangliosides—GSLs containing sialic acids—are incorporated in all animal cell membranes, with the highest content, variety, and specific regional distribution found in the human brain tissue. As important membrane constituents, GSLs confer to its structural rigidity and are also (themselves or as intermediate metabolites) key players in processes such as cell growth, proliferation, differentiation, cell recognition, and apoptosis (16)(17)(18)(19)(20).

Down's syndrome (DS) is used as a comparative model for the study of AD: the same clinical symptoms of dementia and the neuropathological hallmarks characteristic of AD are present in older DS individuals (21). Also, similar biochemical disorders have been observed in both AD and DS nonneural tissues (7).

The aim of this study was to determine possible changes of GSL metabolism in available peripheral cells derived from subjects with a clinical diagnosis of dementia of the Alzheimer type (DAT) and DS.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Subjects
Blood samples were collected at the Department for Neurology, University Hospital "Sestre milosrdnice" in Zagreb, from 19 patients (7 men and 12 women, age range 47–86 years; Table 1 ) with a clinical diagnosis of DAT according to Diagnostic and Statistical Manual (22) DSMIII-R criteria (DSMIII-R 290.21/290.00/290.13/290.10), confirmed by the findings of performed neuropsychiatric tests, laboratory diagnostics, and computerized tomography. Blood samples from 21 individuals (14 men and 7 women, age range 5–52 years; Table 1 ) with a diagnosis of DS, confirmed by caryotyping (trisomy 21), were collected at the Centre for Rehabilitation, Zagreb. Control samples were collected from 26 volunteer blood donors (16 men and 10 women, age range 5–83 years; Table 1 ) with range of diagnoses at the Department for Pediatrics, University Hospital "Sestre milosrdnice" and the Department for Dermatovenerology, University Hospital Center Zagreb, Zagreb. Two age-matched control subgroups were formed because of age differences between DAT and DS subjects: 13 of the 26 volunteer blood donors (age range 47–83 years) were a control group for the DAT patients, whereas 17 of the 26 control individuals (age range 5–56 years) served as a control group for subjects with DS (Table 1 ). All subjects in the control group were free from any neuropsychiatric disorders, as well as from disorders known to interfere with GSL or sulfatide metabolism. Blood was collected from all subjects during morning hours and before any medications were given. Informed consent was taken from each patient and/or his or her caregivers before the investigation. The study was approved by the local ethical committee. All procedures were in accordance with the Helsinki Declaration of 1975, as revised in 1983.


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  		Table 1. Data on Patients With DAT Type and DS, and Control Subjects

 
Isolation of Leukocytes
Leukocytes were isolated from blood samples derived from patients with a diagnosis of DAT (n = 19), DS (n = 21), and individuals without any neurologic or psychiatric disorder as age-matched control groups (CDAT, n = 13; CDS, n = 17). Leukocyte pellets dissolved in 0.25% Triton X-100 were homogenized, and frozen homogenates were stored at -20°C for biochemical analyses.

Determination of Lysosomal Enzyme Activities in Leukocytes
Fluorimetric determination of activities of lysosomal enzymes involved in GSL degradation was performed in leukocyte homogenates on a Perkin Elmer Luminiscence Spectrometer LS50B using methylumbelliferon (MUF) substrates, and the results were expressed as nanomoles of substrate per hour per milligram of protein (nmol h-1 mg-1). The activity of GM1 (II3-{alpha}-Neu5Ac-Gg4Cer) ß-galactosidase (EC [enzyme commission number] 3.2.1.23) was measured by using 4-MUF-ß-D-galactopyranoside as a substrate (23); the activity of GM2 (II3-{alpha}-Neu5Ac-Gg3Cer) ß-hexosaminidase (EC 3.2.1.52) was measured by using 4-MUF-glucos-aminide as a substrate (24), or 4-MUF-N-acetylglucosamine-6-sulfate for izoenzyme ß-hexosaminidase A activity (25). The activity of arylsulfatase A (ASA; EC 3.1.6.1) involved in sulfatide degradation was measured by spectrophotometry ({lambda} = 515 nm), using chromogenic substrate p-nitrocatechol sulfate (26). All necessary substrates and chemicals were purchased from Sigma (St. Louis, MO). Results were statistically analyzed by Student's t test and the Mann–Whitney rank sum test.

Determination of Proteins
The proteins in leukocyte homogenates were determined according to the method of Lowry (27), using bovine serum albumin as standard (BSA, 1 mg ml-1, purchased from Sigma). The results were expressed as milligrams of protein per milliliter of cell homogenate.


   Results
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 Methods
 Results
Discussion
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Activity of Lysosomal Enzymes in Leukocytes in DAT and DS
A statistically significant increase in ß-galactosidase activity was found in both DAT leukocytes (287.37 ± 87.23 nmol h-1 mg-1) in comparison with the age-matched control group (171.89 ± 95.08 nmol h-1 mg-1; p < .01, Student's t test) and DS leukocytes (216.08 ± 97.57 nmol h-1 mg-1) when compared with controls (154.45 ± 50.43 nmol h-1 mg-1, p < .05, Student's t test; Fig. 1). Quantitative results were further analyzed according to defined age groups of DAT, DS, and control subjects. The ß-galactosidase activity was increased in both early (47–62 years) and late onset (70–86 years) DAT cases. This increase was significant in late onset cases (p < .01, Mann–Whitney test; Table 2 ). Increased ß-galactosidase activity was also observed in both young (5–10 years) and older (20–52 years) subjects with DS (Table 2 ). No significant changes were observed in the activity of other enzymes analyzed in DAT and DS leukocytes in comparison with controls (ß-hexosaminidase, ß-hexosaminidase A, ASA; Table 2 ). Gender differences in enzyme activity values were not observed. Also, apolipoprotein E genotyping—performed according to a previously described method (28)—showed no correlation between individual apolipoprotein E genotypes and changes in activities of analyzed lysosomal enzymes.



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  		Figure 1. Activities of ß-galactosidase in leukocytes derived from individuals with diagnosis of A, dementia of the Alzheimer type (DAT, {Delta}), and B, Down's syndrome (DS, {diamond}), in comparison with age-matched controls (C, {circ}). The activity of lysosomal enzymes was measured by fluorimetry and/or spectrophotometry using adequate substrates. Individual values, and mean values with standard deviations (DAT ± SD and DS ± SD) are given. ap < .01; bp < .05, Student's t test.

 

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  		Table 2. Activities of Lysosomal Enzymes in Leukocytes From Patients With a DAT and DS in Comparison With Age-Matched Control Groups

 
Activity of Lysosomal Enzymes in Aging
A slight increase in the activity of ß-galactosidase, ß-hexosaminidase, and ß-hexosaminidase A was observed in control leukocytes with aging (Table 3 ). Statistically significant increase in older versus younger controls was found in the case of ß-hexosaminidase and ß-hexosaminidase A (p < .05, Student's t test). Fig. 2 shows the age-related changes of lysosomal enzyme activities: a continuous increase was observed in the age group of 20–31 years to maximal values in the age group of 56–64 years, and a final decline was observed in the age group of 71–83 years. Increase of ß-hexosaminidase activity persisted even further (71–83 years). In the case of ASA, there was a somewhat different pattern of activities: the continuous decrease was observed from earliest years to the age group of 40–49 years, followed by an increase in the age group of 56–64 years and a decrease in the oldest group (71–83 years).


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  		Table 3. Age-Related Changes of Lysosomal Enzyme Activities in Control Leukocytes

 


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  		Figure 2. Age-related changes of analyzed lysosomal enzyme activities in control leukocytes. The activity of lysosomal enzymes was measured by fluorimetry and/or spectrophotometry using adequate substrates.

 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
Lysosomal Enzymes in Peripheral Cells in AD and DS
Previous studies of brain gangliosides in AD showed specific changes of ganglioside content and composition in analyzed brain regions, explained as a consequence of accelerated degradation of complex gangliosides of neuronal membranes (1)(2). As AD pathology affects both neural and nonneural tissue, the aim of this study was to determine whether similar changes in ganglioside catabolism occur in available peripheral cells in DAT and DS. The results showed a statistically significant increase in ß-galactosidase activity in both DAT (p < .01, Student's t test) and DS (p < .05, Student's t test) leukocytes when compared with age-matched controls. The activities of ß-hexosaminidase and ß-hexosaminidase A in DAT and DS leukocytes slightly differed from age-matched control values. The activity of ASA was slightly decreased in DAT and DS leukocytes in comparison with age-matched controls. The observed decreased activity of ASA in DAT and DS leukocytes is in accordance with published data concerning decreased ASA activity in dementias of various causes, mental retardation, and certain neuropsychiatric disorders (29)(30). As measuring of lysosomal enzyme activities was performed in immunocompetent cells—leukocytes—it is important to mention evidence on local and systemic inflammatory response thought to contribute to or exacerbate the pathogenesis of AD (31)(32). Moreover, there have been certain observations that leukocytes may enter the brain through the still intact blood-brain barrier in several neurological diseases, including AD (33). Also, it is well known that GSLs act as cell surface antigens and are involved in immune recognition processes (16)(17); for instance, immunosuppressive effects and the inhibition of amyloid-induced cytokine release was documented for ganglioside GM1 (34), whereas activation of alternative complement pathway in humans was found for several ganglioside species (35). However, we found no differences in total leukocyte number in DAT and DS patients in comparison with age-matched controls, which is in accordance with data from the study of Song and colleagues (36), who reported similar observations on total number of white blood cells in DAT and elderly control subjects. Although it would be of interest to follow other immune variables and to investigate their contribution to AD pathogenesis, for the time being we concluded that observed changes in GSL and sulfatide degradation by leukocyte lysosomes are not correlated with total number and distribution of white blood cells in DAT and DS patients.

An additional analysis was performed on several DS and age-matched control skin fibroblast cultures established in our laboratory, and one AD (obtained from Coriel Cell Repositories, CCR Number AG00364E, male 61 years) and fetal DS (obtained from European Collection of Animal Cell Cultures, ECACC Number DD1382) culture of skin fibroblasts that were also compared with age-matched human skin fibroblasts. An increased activity of ß-galactosidase and ß-hexosaminidase was observed in both AD and DS fibroblasts in comparison with age-matched control fibroblasts. This increase was more pronounced in AD fibroblasts (quantitative data not shown). Although the number of examined cell cultures was too small for statistical analysis, mentioned preliminary results confirm the possibility of accelerated lysosomal degradative events in different DAT and DS peripheral cells.

In available literature there have been only a few data referring to GSL metabolism in peripheral cells in AD. The study of Maguire and colleagues showed decreased activity of GSL biosynthetic enzymes (sialyltransferases) in both serum (37) and brain tissue (38) in AD and DS as compared with control samples. It may be suggested that both biosynthetic and catabolic pathways of GSLs are altered in mentioned disorders. Previous results on brain gangliosides in AD showed in analyzed brain regions a decrease of GM1 and an increased proportion of GM2, which is the product of GM1 degradation by ß-galactosidase on neuronal membranes (2). From mentioned results and evidence presented here on significantly increased ß-galactosidase activity in DAT and DS leukocytes, we hypothesize that the increase of ß-galactosidase activity most probably occurs also in AD and DS brain tissue. This hypothesis is supported by several immunocytochemical studies, which showed colocalization of several other lysosomal hydrolases and proteases (ß-hexosaminidase A, {alpha}-glucosidase, catepsin D) with ß-amyloid in diffuse plaques in cerebellum and striatum in AD and DS brain tissue (39)(40). A documented increased expression of lysosomal hydrolases in neuronal populations affected by amyloid pathology was explained as a proof for upregulation of endosomal–lysosomal systems and an early marker of metabolic dysfunction related to primary AD etiopathogenesis (40). These findings may support our results, which indicate that similar metabolic disturbances and lysosomal upregulation, at least for analyzed enzymes and material, are present also in nonneural cells in AD and DS. Because of a very complex pathogenesis, which involves interactions of predisposing genetic factors and various environmental influences, the neurodegenerative disorders are characterized by an overlapping of neuropathological findings. Thus, we suggest that the acceleration of lysosomal degradative pathways in neural and nonneural tissues is most probably an event that accompanies other neurodegenerative disorders other than AD or DS.

Lysosomal Enzymes and Aging
Another finding is related to changes of analyzed lysosomal enzyme activities in control leukocytes with aging. According to our knowledge, there are no recent systematic data on activities of these enzymes during aging. There is some evidence that other lysosomal enzymes, such as acid phosphatase, ß-glucuronidase, and N-acetyl-ß-glucosaminidase, are increased in old human lymphocytes (41), whereas activities of ß-galactosidase, ASA, and ß-D-glucuronidase were found to decrease in the human liver with aging (42). In conclusion, different enzymes show different activity patterns with aging, depending on tissue type and origin (43). However, the majority of lysosomal enzymes show increased activities during aging, which is related to the degradation of lysosomal membranes. Our results showing increased activities of ß-galactosidase, ß-hexosaminidase, and ß-hexosaminidase A in control leukocytes with aging are in accordance with reported data and can be explained in the same manner. Also, one of the recent studies reported histochemical identification of ß-galactosidase as a biomarker of senescence in human skin fibroblasts and in aging skin in vivo (44). Although the authors made a distinction between two forms of ß-galactosidase—one that is histochemically expressed at pH = 6, and lysosomal ß-galactosidase, which is expressed at lower pH values—it may be assumed that detected ß-galactosidase expression is related to lysosomal upregulation and/or liberation of lysosomal enzymes into the cytoplasm of senescent cells. Furthermore, the same paper makes the observation that senescent cells expressed threefold to fivefold more lysosomal ß-galactosidase mRNA (44). Our quantitative data on increased ß-galactosidase activity in leukocytes and skin fibroblasts derived from older subjects support the histochemical detection of increased ß-galactosidase expression in senescent cells.

Conclusions
In conclusion, the results of this study indicate a disturbed or accelerated glycosphingolipid degradation in analyzed DAT and DS leukocytes and cultured skin fibroblasts. Finally, although an increase of the analyzed lysosomal enzyme activities in peripheral cells accompanies normal aging, this increase was found to be significantly more pronounced in dementia of the Alzheimer type and Down's syndrome—disorders in which pathological aging processes seem to occur.


   Acknowledgments
 
The study was supported by the Croatian Ministry of Science and Technology and the Open Society Foundation—Croatia. Gangliosides are abbreviated according to the nomenclature of Svennerholm (45) and the recommendations of the International Union of Pure and Applied Chemistry and International Union of Biochemistry (46).

We thank Dr. I. Gluhak and employees of the Centre for rehabilitation; Drs. Lj. Cvitanovic-©ojat and T. Baudouin from the University Hospital "Sestre milosrdnice"; Drs. D. Anticevic and A. Pasic from the University Hospital Centre in Zagreb for help in collecting the material; Dr. K. Fumic from the Clinical Centre for Laboratory Diagnostics, University Hospital Centre in Zagreb, for enabling the use of necessary equipment; and Mrs A. »acic and Ms. S. Gavrilovic for technical assistance.

Received February 21, 2001

Accepted August 14, 2001


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