neurochemical aspects of alzheimer's disease: involvement...

Metabolic Brain Disease, Vol. 3, No. 1, 1988

Review Article

Neurochemical Aspects of Alzheimer's Disease: Involvement of Membrane Phospholipids

Akhlaq A. Farooqui, 1'2 Leopold Liss, 3 and Lloyd A. Horroeks I

INTRODUCTION

Alzheimer's disease is a slowly progressive, dementing disorder with the pathological hallmarks of cerebral cortical atrophy, senile plaques, neurofibrillary tangles, and granulovacuolar changes. The demonstration that these pathological changes are frequently associated with dementia in the elderly has led to the recognition of Alzheimer's disease as one of the most common seriously disabling neurological disorders (Sinex and Merril, 1982; Katzman, 1986; Terry and Katzman, 1983). Generally, the onset of Alzheimer's disease is heralded by impairments in recent memory. Affected individuals may be able to recall considerable detail from the distant past, but they cannot remember what occurred just minutes earlier (Terry and Katzman, 1983). The etiology and pathogenesis of Alzheimer's disease remain unknown. However, the following causative factors should be carefully considered (Wurtman, 1985): (i) aging in general, (ii) transmissible agents called viroids, (iii) hereditary and familial predispositions, (iv) Down's syndrome, (v) environmental toxins such as aluminum in brain, (vi) a decrease in blood flow, and (vii) a decrease in acetylcholine in brain. Each of these primary etiologies may contribute to the specific changes which result in Alzheimer's disease.

CHOLINERGIC SYSTEMS

There are several lines of evidence indicating a marked cholinergic deficiency in brain tissue of Alzheimer's patients (Davies and Maloney, 1976). It has been well

~Department of Physiological Chemistry, The Ohio State University, Columbus, Ohio 43210. 2 To whom correspondence should be addressed at Department of Physiological Chemistry, The Ohio State University, 1645 Neil Avenue, Room 214, Columbus, Ohio 43210.

3Department of Pathology, The Ohio State University, Columbus, Ohio 43210.

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0885-7490/88/0300-0019506.00/0 �9 1988 Plenum Publishing Corporation

20 Farooqui, Liss, and Horrocks

established that choline acetyltransferase (choline + acetyl CoA ~ acetylcholine + CoA) is diminished 50 to 90% in neocortex and hippocampus of affected brain (Bowen et al., 1976; Perry et al., 1977). These studies have atso indicated that the extent of choline acetyltransferase deficiency correlates with the severity of dementia in Alzheimer's disease (Wilcock et aI., 1982). The regulatory step in acetylcholine synthesis does not seem to be the choline acetyltransferase-catalyzed reaction (Tucek, 1985) but rather the supply of acetyl CoA and transmembrane passage of choline into the terminal. The amount of acetylcholine in the cholinergic nerve cell therefore reflects the position of the mass-action equilibrium, which is itself dependent on the intra- terminal acetyl CoA and choline concentrations. Sims et al. (1981) have recently demonstrated that acetylcholine itself is diminished in biopsy samples of Alzheimer's disease. Moreover, a deficit of acetylcholinesterase has also been found in brains of demented patients (Davies, t979). Although acetylcholinesterase is enriched in cholinergic neurons, it is also present in some nerve cells which do not utilize acetylcholine; for this reason, acetylcholinesterase is not considered a marker specific for cholinergic neurons (Butcher et al., 1975).

Additional evidence supporting the view that there is a cholinergic deficit in Alzheimer's disease is provided by studies on the effects of cholinesterase inhibitors such as physostigmine which improve memory retention abilities in both experimental animals and humans (Davis et al., 1978), indicating that central cholinergic neuro- transmission may play a role in the processing of recent memories, and abnormalities of this system may underlie some of the symptomatic manifestations of this disease. The delineation of cholinergic deficits in Alzheimer's disease along with the selective degeneration of nerve cells in the diagonal band of Broca and nucleus basalis of Meynert (Coyle et aL, 1983) provides an excellent example of a major disorder of higher cognitive functions in which transmitter-defined neuronal pathways responsible for dementia have been identified.

CATECHOLAMINERGIC SYSTEMS

Several studies (Adolfsson et al., 1979) have indicated a significant decrease in the noradrenaline concentration in various brain regions. The activity of dopamine /Lhydroxylase is also decreased in various brain regions, serum, and cerebrospinal fluid of Alzheimer's patients (Cross et al., 1981; Miyata et at., 1984). The loss of noradrenaline and dopamine 3-hydroxylase in the cortex could well be the result of degeneration of cell bodies in the locus coeruleus (Mann et al., 1980). Although the evidence points to the view that there is some noradrenergic loss in Alzheimer's disease, the position of dopamine is less clear. Gottfries et al. (1969) first reported that the neostriatum and cerebrospinal fluid (CSF) of patients with Alzheimer's disease contain decreased contents of homovanillic acid and 5-hydroxyindole acetic acid, suggesting a reduced turnover of dopamine and 5-hydroxytryptamine. However, the actual concentrations of dopamine in the caudate nucleus and substantia nigra of patients with Alzheimer's disease do not seem to be altered (Yates et al., 1979). It may be possible that observed alterations in catecholaminergic systems are due to

Aizheimer's Disease 21

cholinergic cell loss in the caudate nucleus rather than to primary dopaminergic cell loss. Burk et al. (1987) have recently reported a decrease of 37 to 48% in phenyl- ethanolamine N-methyltransferase activity in areas of the brain affected with Alzheimer's disease but not in the cerebellum.

Recent studies by Cowburn et al. (1987) have indicated a severe loss of both GABAergic and glutamatergic terminals in cortical and hippocampal regions in Alzheimer's disease with little or no deficit in subcortial regions. Such deficits are consistent with the pathology of Alzheimer's disease (Mann et al., 1985).

D'Amato et al. (1987), on the basis of [3H]citalopram binding (a more selective serotonin uptake inhibitor) to serotininergic uptake sites and decreased levels of serotonin, have indicated that serotoninergic neurons are substantially damaged in Alzheimer's disease patients.

N E U R O P E P T I D E S IN ALZHEIMER'S DISEASE

Recent investigations have also indicated that two putative neurotransmitters have been consistently deficient in Alzheimer's disease. These are somatostatin (Davies et al., 1982) and substance P (Rossor et al., 1980). Since the roles of somatostatin and substance P in cortex are unknown the metabolic significance of their deficiencies is not fully understood (Beal and Martin, 1986).

All of these changes in neurotransmitters are most likely a result of loss of neurons and are not a direct cause of the disease. The problem is to discover the cause of the degeneration of neurons.

LIPIDS IN N O R M A L AGED H U M A N BRAIN

Phospholipids constitute a biologically important group of molecules which forms the backbone of all cellular membranes (Porcellati, 1983). In adult brain, they account for about 20 25% of the dry weight. They not only constitute the backbone of the biomembrane but also provide the membrane with a suitable environment, fluidity, and ion permeability. The phospholipid bilayer is penetrated to varying degrees by receptors, enzymes, and ion channels, which differentially protrude through the membrane or are localized predominantly on the intracellular or extra- cellular membrane surface. Different phospholipids turn over at different rates with respect to their structure and localization in different cells and membranes (Porcellati et al., 1983; Farooqui and Horrocks, 1985). These membranes are highly interactive and dynamic. The interaction of ligand with receptor-linked enzymes markedly affects neural membrane lipid metabolism, which in turn regulates the microenvironments of membrane-bound enzymes and ion channels (Porcellati, 1983; Farooqui and Horrocks, 1985).

The Concentrations of most lipids in human brain decrease at nearly constant rates after the age of 50 years, but with different rates for different lipids (Table I).


Ta~e 1. Relative Decrease in Lipid Concentration in Male Human Brain During Aging a

Percentage loss Concentration,

Lipid age 40 Age 70 Age 100

Cholesterol 66.2 11 17 Cerebrosides 22.9 14 24 Cerebroside 3-sulfate 7.9 19 48 Lipid phosphorus 69.9 7 11 Choline glycerophospholipids 20.8 5 8 Ethanolamine plasmalogens 15.4 18 29 Phosphatidylethanolamine 9.2 2 3 Serine glycerophospholipid I 1.9 10 16 Sphingomyelin 10.0 12 20

~ from Horrocks et aL (1981).

This results in changes in lipid composition during aging. Higher rates of loss are found for lipids in which myelin is relatively enriched. Between 40 and 70 years of age, losses are from 10 to 20% for cerebroside 3-sulfate, ethanolamine plasmalogens, cerebrosides, sphingomyelins, cholesterol, and serine glycerophospholipids. Very little loss is found for other phospholipids including choline glycerophospholipids, phosphatidylethanolamine, inositol glycerophospholipids, and phosphatidic acids. Ratios of cholesterol and lipid galactose to lipid phosphorus do not change in cerebral white matter after 20 years of age.

In addition to the decrease in the total lipid content of the human brain, significant aging changes occur in the fatty acid (acyl-group) composition of brain lipids. A time-dependent change in the acyl-group composition of the phospholipids (long-chain fatty acid moieties linked to phosphate groups) in the myelin sheath may be one of the mechanisms of aging in the mammalian brain (Sun and Samorajski, 1973). Some drugs believed to stimulate cerebral metabolism also have marked effects on lipid metabolism in older animals.

Although specific acyl-group profiles are associated with each phospholipid, the most significant age-related differences are found in ethanolamine glycerophospholipids, a major class of brain phospholipid. Ethanolamine glycerophospholipids, which constitute about 40% of the myelin phospholipids, contain most of the unsaturated acyl groups found in myelin (Sun and Samorajski, 1973). The acyl-group composition of ethanolamine glycerophospholipids (EGP) in myelin from three age groups of mice, rhesus monkeys, and humans were studied by Samorajski and Rolsten (1973) and Sun and Samorajski (1973), who found that the older age groups of all three species had higher proportions ofmonoenes (mainly 18 : 1 and 20: 1) and lower proportions of polyenes (mainly 20 : 4 and 22 : 4). A decrease with age also occurs in polyunsaturated acyl groups of EPG isolated from frontal gray matter (Bowen et al., 1973). In addition to an increased ratio of saturated to unsaturated acyl groups, the chain length of some fatty acids may increase with age, particularly in the glycero- lipids (Dhopeshwarkar and Mead, 1975). Considered together, the changes in the acyl-group composition of myelin phospholipid are small, but they may be important in determining the functional properties of myelin and other types of membranes during aging.

Alzheimer's Disease 23

LIPID C H A N G E S IN ALZHEIMER'S DISEASE

Early work on lipid alterations in senile dementia has been extensively reviewed by Embree et al. (1972). Several studies have placed special emphasis on decrements in ganglioside, a sialic acid-containing glycolipid, shown to be enriched in neuronal plasma membranes and to have a markedly diminished content in tissue specimens from Alzheimer brain (DeKosky and Bass, 1982; Bowen et al., 1976; Suzuki et al., 1965). Both age-related losses of ganglioside and the greater loss of ganglioside in Alzheimer's disease appear to affect the lower laminae of the cortex more than the upper laminae (DeKosky and Bass, 1982; Svennerholm et al., 1988). They may be related to the loss of large neurons as reported by Terry et al. (1982) and Mountjoy et al. (1983), with attendant loss of the large dendritic arbors of such neurons.

Other lipid membrane components, such as phospholipids and cholesterol, show relatively minor changes in Alzheimer's disease. Suzuki et aL (1965) and Suzuki and Chen (1966) found a significant decrease in ethanolamine glycerophospholipids using classical procedures for the extraction and separation of phospholipids. Ellison et aL (1987) measured phosphoethanolamine and ethanolamine in postmortem brain samples from patients with Alzheimer's disease and found 64, 48, and 40% decreases in the phosphoethanolamine content of the temporal cortex, frontal cortex, and hippocampus, respectively. In contrast, Miatto et al. (1986, 1988) studied the phospholipid composition of brain from Alzheimer's disease patients using nuclear magnetic resonance (NMR) spectroscopy and found a significant increase in levels of glycerophosphocholine which may be a product of choline glycerophospholipid catabolism. Choline and ethanolamine plasmalogens are important constituents of mammalian brain (Horrocks et al., 1987). These metabolites are very active metabol- ically and may be involved in receptor-mediated release of arachidonic acid and subsequent formation of eicosanoids (Horrocks et al., 1986). Ether-linked choline glycerophospholipids containing alkyl groups are precursors of platelet activating factor. Phosphatidylinositols are another group of membrane constituents that are involved in signal transduction process (Sekar and Hokin, 1986). At present no information is available on the levels of ethanolamine plasmalogens and choline glycerophospholipids in human brain, and Stokes and Hawthorne (! 987) have recently found reduced concentrations of phosphoinositide in the anterior temporal cortex of 17 patients with Alzheimer's disease compared to age-matched normal human brain. It has been suggested that the lack of phosphoinositides in Alzheimer's temporal cortex may impair receptor functions. We have recently developed state-of-the-art methodology (Saunders and Horrocks, 1984; Dugan et al., 1986) for the extraction and separation of various lipids and phospholipids from mammalian brain. Separation of various phospholipids from membrane preparations of normal and Alzheimer's disease brain by the above procedures (Saunders and Horrocks, 1984; Dugan et al., 1986; Horrocks et al., 1987) would lead to a better understanding of lipid metabolism in senile dementia.


AUTOCANNIBALISM HYPOTHESIS OF BLUSZTAJN ET AL. (1984) FOR THE PATHOGENESIS OF ALZHEIMER'S DISEASE

In nerve cells the choline molecule plays a multiple role--it not only is a transmitter precursor but also can be incorporated into important membrane constituents (phosphatidylcholine and sphingomyelin). The existence of different uptake systems, pools, and complicated metabolic relationships makes studies in vitro and in vivo difficult. Furthermore, there is some uncertainty concerning even the source of choline for the synthesis of acetylcholine. Under resting conditions the free choline pool seems to be sufficient to maintain acetylcholine synthesis, but during enhanced function other pools may be mobilized (Trommer et al., 1982). Although the nature and sites of these pools have not yet been characterized, the possibility that in certain circumstances the membrane phospholipids are able to liberate choline has been proposed (Schmidt and Wecker, 1981). Recently Blusztajn et al. (1984) have proposed a novel hypothesis on the possible role of neuronal choline metabolism in the pathophysiology of Alzheimer's disease. According to this hypothesis, when free choline is in short supply (relative to the amount needed for acetylcholine synthesis), cholinergic neurons may break down the phosphatidylcholine in their membranes more rapidly than they can synthesize it, thereby either diminishing membrane phosphatidylcholine levels relative to other phospholipids or reducing the ability of the cell to synthesize new membrane. Either change might be expected to impair membrane functions especially in the aged brain, whose membranes already contain abnormal quantities of cholesterol and phospholipids other than phosphatidylcholine; this impairment might contribute to the neuron's untimely demise. A corollary of this hypothesis might be that the administration of supplemental choline to patients with Alzheimer's disease might--besides amplifying the release of acetylcholine from surviving cholinergic terminals (Ulus and Wurtman, 1979; Bierkamper and Goldberg, 1980)--redress the imbalance between phosphatidylcholine breakdown and its synthesis, thereby sustaining membrane composition, slowing the disease process, and ameliorating deficits in acetylcholine-dependent brain functions.

The degradation of phosphatidylcholine in neurons can occur by several pathways (Fig. 1). Phosphatidylcholine can be hydrolyzed directly to choline by phospholipase D (reaction 3 in Fig. 1) (Saito and Kanfer, 1975). This enzyme is stimulated by free fatty acids (Chalifour and Kanfer, 1982), which, in turn, may arise from the action of phospholipases AI and A2 on phosphatidylcholine. Phospholipase A 2 is increased in various pathological conditions (Farooqui et al., 1987) and when various plasma membrane receptors are activated and may be a rate-limiting step in the synthesis of prostaglandins (van den Bosch, 1980). Thus the stimulation of phospholipase A2 may, by enhancing fatty acid accumulation, activate phospholipase D and thus accelerate the liberation of choline from phosphatidylcholine. Lysophosphatidyl choline formed by phospholipases AI and A2 can be further hydrolyzed to free choline by lysophospholipase D (reaction 4, Fig. 1) (Wykle and Schremmer, 1974) or metabolized to glycerophosphocholine by a lysophospholipase (reactions 5, Fig. 1) (Leibowitz-Ben Gershon and Gatt, 1972). This metabolite is then hydrolyzed either by a glycerophosphocholine phosphohydrolase (Abra and Quinn, 1975) or by a glycerophosphocholine diesterase (Webster et al., 1957) to free choline.


Phosphatidylcholine

PA 12

1 / I I 3 DAG " " J ~ ,~ CDP-Choline

/ /73\ Xr \ / / / i \ & L00 e o 0e (/ / I

Lysophosphatidyl > Glycerophospho- 6 ) Phosphocholine Choline 5 Choline

Fig. 1. Hypothetical scheme showing the role of lipases and phosphotipases in controlling the concentration of choline in brain. (1) Phospholipases A] and A2; (2) phospholipase C; (3) phospholipase D; (4) lysophospholipase D; (5) lysophospholipase; (6) glycerophosphocholine phosphodiesterase; (7) alkaline phosphatase; (8) diacylglycerol lipase; (9) monoacylglycerol lipase; (10) diacylglycerol kinase; (11) phosphochotine cytidylyltransferase; (12) choline phosphotransferase.

Finally, phosphocholine can also be hydrolyzed to free choline by phosphocholine phosphatase (reaction 7, Fig. 1) (Ansell and Spanner, 1968a). So it seems quite likely that the activities of phosphatidylcholine phospholipases may be markedly affected in Alzheimer's disease. This suggestion is also supported by recent work on measles virus (Suzuki and Matsumoto, 1982) which indicates that the activities of phospholipases are increased several fold in response to viral infection [see the infectious-agent model of Alzheimer's disease by Wurtman (1985)].

LIPASES IN ALZHEIMER'S DISEASE

We have recently obtained autopsy samples from several normal human and Alzheimer's patient brains and have isolated plasma membrane (PM) and synaptosomal plasma membrane (SPM) from different regions. The assays of these membranes for lipases in normal subjects and Alzheimer's disease (AD) patients brain indicate that both PM and SPM contain mono- and diacylglycerol lipases (Tables II-IV). Among the various regions analyzed, membrane from the nucleus basalis displayed the highest enzymic activity. The activities of mono- and diacylglycerol lipases were always higher in the SPM compared to the PM fraction. Mono- and diacylglycerol lipases were uniformly distributed in the PM and SPM fractions of frontal, parietal, and occipital cortex and corpus callosum. Membranes from


Table II. Activities of Monoacylglycerol Lipases in Plasma Membrane (PM) and Synaptosomal Plasma Membrane (SPM) Fractions of Alzheimer's Disease Autopsy Brain a

Monoacylglycerol lipase (nmol/min/mg protein)

Normal

Region (5) (6) (7) (8) (9) (10) (11) (12)

PM Nucleus basalis 29.75 32.53 15.59 17.73 25.83 28.32 4.59 3.97 Caudate nucleus 2.62 2.07 1.97 3.17 2.74 2.06 2.43 1.97 Frontal cortex 5.93 4.56 7.21 5.97 5.37 6.68 3.87 2.41 Parietal cortex 3.27 4.88 5.63 4.48 6.47 5.79 5.06 3.71 Occipital cortex 4.93 8.97 8.92 6.16 5.21 4.83 4.93 2.46 Hippocampus 15.71 20.48 10.31 11.57 18.61 16.57 3.16 2.56 Corpus callosum 3.48 2.79 4.31 4.86 5.06 3,97 5.94 1.99

SPM Nucleus basalis 39.57 40.81 29.54 35.31 47.83 51.39 6.97 4.57 Caudate nucleus 3.57 4.01 3.84 3.42 4.06 2.97 3.63 2.16 Frontal cortex 9.61 6.27 7.98 7.12 8.16 5.37 5.93 3.73 Parietal cortex 8.93 8.93 6.73 8.97 6.97 7.56 6.21 4.06 Occipital cortex 7.62 7.63 8.82 4.16 5.16 8.97 7.98 2.51 Hippocampus 21.31 19.78 17.41 14.68 23.72 27.84 9.71 3.56 Corpus callosum 6.21 5.93 4.82 5.71 6.42 8.57 4,06 2.11

"Brains were processed for the isolation of PM and SPM at 4-7 hr after death. The numbers in parentheses are autopsy numbers. Taken from Farooqui et al. (1988).

Table IlL Activities of Diacylglycerol Lipase in Plasma Membrane (PM) and Synaptosomal Plasma Membrane (SPM) Fractions of Alzheimer's Disease Autopsy Brain a

Diacylglycerol lipase (nmol/min/mg protein)

Normal

Region (5) (6) (7) (8) (9) (10) (1 I) (12)

PM Nucleus basalis 18.32 23.76 4.52 3.72 26.20 24.53 2.82 3.52 Caudate nucleus 2.53 4.21 1.25 1.88 2.73 4.05 1.57 1.39 Frontal cortex 5.57 4.31 3.52 4.06 4.60 3.21 2.51 1.99 Parietal cortex 4.51 5.12 4.73 4.34 5.57 4.95 2.34 1.92 Occipital cortex 4.89 3.56 2.06 4.92 4.21 3.51 2.37 2.05 Hippocampus 8.53 9.57 4.17 2.57 6.92 7.39 2.53 1.88 Corpus callosum 2.16 4.03 1.43 1.52 2.63 2.21 1.43 2.2t

SPM Nucleus basalis 23.62 40.78 11.78 10.52 35.82 38.43 3.57 3.92 Caudate nucleus 2.21 2.21 2.53 2.92 2.82 3.03 2.36 2.73 Frontal cortex 4.21 3.92 2.97 5.96 2.57 3.92 ! .92 1.67 Parietal cortex 6.41 4.52 3.52 4.52 4.21 4.93 1.54 1.77 Occipital cortex 5.83 7.19 3.15 5.98 5.10 3.98 1.75 1.89 Hippocampus 7.21 6.92 5.21 4.92 8.77 12.21 3.92 3.57 Corpus callosum 2.57 3.12 1.59 2.21 2.93 2.99 1.92 2.01

aBrains were processed for the isolation of PM and SPM at 4-7 hr after death. The numbers in parentheses are autopsy numbers. Taken from Farooqui et al. (1988).

AIzheimer's Disease 27

Table IV. Activities of Lysophospholipase in the Cytosolic Fraction of Brain from Alzheimer's Disease ~'

Lysophospholipase (nmol/min/mg protein)

Normal

Region (5) (6) (7) (8) (9) (10) (1 I) (12)

Nucieus basalis 31.31 25.97 5.93 4.94 30.57 27.16 6.93 5.31 Caudate nucleus 5.61 4.97 3.91 5.61 6.21 5.71 5.16 4.93 Frontal cortex 6.31 5.93 8.56 4.97 4.63 4.31 3.72 2.93 Parietal cortex 5.97 6.21 4.29 8.16 8.79 5.42 4.68 3.71 Occipital cortex 4.81 5.16 6.57 4.68 4.43 4.27 5.97 4.06 Hippocampus 12.31 9.71 7.52 8.41 18.64 15.41 4.63 2.78 Corpus callosum 5.71 4.31 3.97 2.59 4.83 3.97 4.21 3.59

~Cytosolic fraction was prepared 4-7 hr after death from the above regions of human brain. The numbers in parentheses are autopsy numbers. Taken from Farooqui et al. (1988).

caudate nucleus displayed the lowest activities of mono- and diacylglycerol lipases. The activities of lipases were six to eight times higher in the PM and SPM fractions of nucleus basalis from Alzheimer's brain autopsy than in the corresponding fractions of normal human brain. Membranes from the hippocampus region of Alzheimer's autopsy brain also showed consistently higher activities of mono- and diacylglycerol lipases than membranes from hippocampus of normal human brain autopsy. Similarly, lysophospholipase activity of cytosolic fraction of these regions also showed higher (five- to sixfold) activity than corresponding fractions from normal human brain. Increased lysophospholipase activity correlates well with increased levels of glycerophosphocholine in Alzheimer's disease (Miatto et al., 1986, 1987). The cause of increased activities of lipolytic enzymes in nucleus basalis and hippocampus is not understood. However, the enhanced activities of lipolytic enzymes may be due to alterations in the levels of neuropeptides in Alzheimer's brain autopsy (Beal and Martin, 1986). Certain neuropeptides such as fl-endorphin, bradykinin, and angiotensin, are known to increase lipolysis through the activation of lipolytic enzymes (Jean-Baptiste and Rizack, 1980; Schwandt et al., 1981; Richter e t al., 1983; Gecse et al., 1987).

Increased activities of lipolytic enzymes in membrane fractions of AD brain may be due to alteration in levels of calcium ions (Peterson et al., 1985; Peterson and Goldman, 1986). Furthermore, lipid peroxidation may play a major role in central nervous system aging, including the changes involved in the pathogenesis of AD (Harman et al., 1976; Eddy and Harman, 1977; Harman, 1984; Clausen, 1984; Cole and Timiras, 1988). Peroxidative membrane injury usually results from the reaction of free radical species with proteins and unsaturated lipids in the plasma membrane, leading to a chemical cross-linking of membrane proteins and lipids and a reduction in membrane unsaturated lipid content. This depletion of unsaturated lipids is associated with alterations in membrane fluidity (Bruch and Thayer, 1983) and changes in the activity of membrane-bound enzymes and receptors (Heikkila, 1983; Bobik et al., 1983). Also, lipid peroxidation stimulates activities of lipolytic enzymes including phospholipases A2 and C (Sevanian and Kim, 1986; Scott, 1984; Sevanian, 1986; Beckman et al., 1987). So it may be possible that in AD brain lipid peroxidation


stimulates the activities of lipolytic enzymes. In fact, Scott (1984) and Van Kuijk et al.

(1987) have proposed a novel role for lipotytic enzymes (phospholipase A2) in protect- ing the membranes from oxidative injury and in maintaining a normal membrane composition, fluidity, and flexibility.

Kanfer et al. (1986) have recently shown that brain homogenates from AD patients show a 63% decrease in phospholipase D activity compared to controls, indicating a compromised metabolism of choline-containing metabolites in patients with Alzheimer's disease. This may be a cause of relative choline deficiency for acetylcholine synthesis, as proposed by Wurtman et al. (1985), and the enhanced lipolytic activities observed in these experiments may represent compensatory mechanisms of choline production via the phospholipase Az/lysophospholipase or phospholipase C/diacylglycerol lipase/phosphocholine phosphatase cascades.

Plasmalogenase Activity in Alzheimer's Disease

In white matter and myelin, the most prevalent phospholipid type is ethanolamine plasmalogen, which accounts for one-third of the phospholipids (Horrocks, 1972; Horrocks and Fu, 1977). In many studies of demyelination, the first change in myelin lipid composition is a loss of ethanolamine plasmalogens and the earliest enzymic change that has been detected is an increase in plasmalogenase activity. Ansell and Spanner (1965) discovered this enzyme that cleaves the vinyl ether moiety of ethanolamine plasmalogens.

Biopsy samples were obtained of frontal lobe white matter from five patients with Alzheimer's disease (Horrocks et at. , 1978). These tissues, like those from multiple sclerosis patients, had twice as much plasmalogenase activity as was found in the control white matter (Table V). White matter from Alzheimer's disease had a 38% lower plasmalogen concentration than was found in normal tissues (Table VI). Presumably the lower plasmalogen concentration in white matter from Alzheimer's disease is due to the increased activity of plasmalogenase. Plasmalogen concentrations were not decreased in white matter from subjects with multiinfarct senile dementia or

Table V. Plasmalogenase Activities in Normal and Demyelinating Human White Matter a

Activity, Brain region #mol (g tissue)-l (hr)-I

Normal Corpus callosum 0.90 Frontal lobe 0.85-0.90

Multiple sclerosis Corpus callosum 1.90 Frontal lobe 1.81

Alzheimer's disease Frontal lobe 1.92 + 0.26 (5) b

aTaken from Horrocks et al. (1978). The results for multiple sclerosis and the assay method are from Ansell and Spanner (1968a, b).

bMean _+ SD.


Table VI. Plasmalogen Concentrations in Human Frontal Lobe White Matter c'

Plasmalogens, Subjects ~tmol (g tissue)-

Normal 28 Alzheimer's disease 17.3 + 4.2 (6) Multiinfarct dementia 31.9, 29.5 (2) Cerebral atrophy 26.0

"Taken from Horrocks e t al. (1978).

cerebral atrophy without Alzheimer's disease. The pathogenesis of Alzheimer's disease is not yet established but the demyelination that may be mediated by plasmalogenase could be involved in the dementia by disruption of neuronal connec- tions. This is supported by the work of Fu et al. (1980), who found that the activity of plasmalogenase is increased five fold in early demyelinating lessions from white matter of dogs injected with distemper virus. These observations strongly suggest that plasmalogenase may be involved in demyelinating processes. Further, the ethanolamine plasmalogen content of cat spinal cord is markedly decreased after spinal cord trauma (Demediuk et al., 1985), probably due to the activation of plasmalogenase.

THERAPEUTIC EFFECT OF LIPIDS IN ALZHEIMER'S DISEASE

Effects of PtdCho Administration

Attempts have been made to treat Alzheimer's disease by giving large doses of phosphatidylcholine (PtdCho) or choline, in the hope of thereby enhancing acetylcholine synthesis in affected neurons. However, the results of administering these substances have been controversial. Several investigators (Marchbanks, 1982; Canter et al., 1982; Wettstein, 1983) found no improvement in behavior, recent memory, or other neuropsychological functions. On the other hand, Wood and Allison (1982) and Neri et al. (1985) concluded that phosphatidylcholine administration may be useful for the improvement of several cognitive functions including memory and behavior in Alzheimer's disease patients. Further, it has also been reported that the age- dependent impairment in memory-performance that is observable in normal human subjects over 40 years may be improved by feeding them phosphatidylcholine. Further trials are required to determine the usefulness of PtdCho therapy in Alzheimer's disease.

Effects of PtdSer Administration

Toffano et al. (1978) were the first to report the beneficial effects of phosphatidylserine (PtdSer) in the aging brain. Thus exogenous PtdSer not only increases dopamine release from the dopaminergic terminal of rat striatum but also stimulates


acetylcholine release from rat cerebral cortex (Mazzari and Battistella, 1980; Caramenti et al., 1979). Calderini et al. (1986) have recently reported that PtdSer treatment can improve the memory function altered by the aging process. The increase in memory function is paralleled by a normalization of the electroencephalographic profile, suggesting a close relationship between the two events. Further, morpho- logical studies have indicated that aging brain shows a marked reduction in the number of neuronal dendritic spines and PtdSer prevents this process. Thus rats treated with PtdSer from 3 until 27 months of age did not show any reduction of the dendritic spines in comparison with young control animals (Nunzi et al., 1987).

In humans the treatment of Alzheimer's disease and related cognitive disorders (Palmieri et al., 1985; Filetti et al., 1983) with PtdSer has positive effects on a number of cognitive performance tests and daily living activities. The most recent study on the treatment of Alzheimer's disease by PtdSer was done by Amaducci (1987), who reported statistically significant improvement on a variety of neuropsychological tests in severe cases of dementia. Thus determination of PtdSer in normal and Alzheimer's disease would result in a better understanding of the therapeutic value and of the metabolism of this phospholipid in human brain.

Effects of Ganglioside Administration

Studies from Svennerholm's group (Svennerholm et al., 1987) have indicated that gangliosides may produce beneficial effects in Alzheimer's disease patients. It has been indicated that intramuscular injections of gangliosides delay the disease process but do not cure the Alzheimer's disease. How much injected ganglioside enters the brain and how the gangliosides produce improved behavioral changes in Alzheimer's disease patients remain unknown. However, it has been speculated that gangliosides may stabilize neural membranes, produce increased sprouting and plasticity and regeneration of degenerating neurons (Katoh-Semba et al., 1984; Toffano et al., 1984).

In conclusion, while the therapeutic approaches of stimulating the surviving cholinergic neurotransmitter system or stabilizing the membranes of degenerating neuron in Alzheimer's disease (PtdCho, PtdSer, or ganglioside therapy) have a strong logic, the results to date are not very encouraging. The possibilities for further exploiting the above approaches are, numerous however, and undoubtedly many new trials using newly discovered drugs or cocktails of existing drugs should be carried out. Nevertheless, it must be emphasized that the above treatments are unlikely to reverse the Alzheimer's disease. These agents may delay the disease process and produce their beneficial effect by interacting with the degenerating neurons.

It seems obvious that the best way to find a real solution to the problem posed by Alzheimer's disease would be to succeed in identifying a causative agent(s) or etiological factor(s), amenable to control. This not only would permit prevention but also would result in the discovery of specific treatment.

A|zheimer's Disease 31

A C K N O W L E D G M E N T S

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NS-10165 and g ran t s f r o m the A m e r i c a n H e a l t h Ass i s t ance F o u n d a t i o n and O h i o

D e p a r t m e n t o f Ag ing , S ta te o f Oh io .

R E F E R E N C E S

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