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1. |
Immune dysfunctions: New targets of drug discovery for alzheimerapos;s disease and other cognitive disorders |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 95-99
Harbans Lal,
Michael J. Forster,
Konrad C. Retz,
Barry Reisberg,
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摘要:
AbstractThe development of treatments applicable to Alzheimerapos;s disease and other age‐associated dementias represents a serious challenge to biomedical research. It is suggested that advances in the understanding of basic etiologic mechanisms in these disorders would provide the most direct avenues to discovery of preventive and arrestive treatments. An overview of research relating to the potential involvement of immune dysfunctions in the etiology of Alzheimerapos;s and other central nervous system (CNS) diseases is reviewed as this was presented and discussed in a recent satellite symposium, “Autoimmunity: Its Role in Alzheimerapos;s Disease and Other Behavioral Dysfunctions,” held at the 17th Annual Meeting of The Society for Neuroscience. It is predicted that some future research may focus on immunological dysfunctions as targets for the discovery and development of drugs for treatment of Alzheimerapos;s dieseas and other cognitive diso
ISSN:0272-4391
DOI:10.1002/ddr.430150202
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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2. |
Stage‐specific behavioral, cognitive, and in vivo changes in community residing subjects with age‐associated memory impairment and primary degenerative dementia of the Alzheimer type |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 101-114
Barry Reisberg,
Steven H. Ferris,
Mony J. de Leon,
Elia Sinaiko Emile Franssen,
Alan Kluger,
Pervez Mir,
Jeffrey Borenstein,
Ajax E. George,
Emma Shulman,
Gertrude Steinberg,
Jacob Cohen,
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摘要:
AbstractStage‐specific relationships between the seven‐stage Global Deterioration Scale (GDS) for age‐associated memory impairment and primary degenerative dementia of the Alzheimerapos;s type and behavioral, cognitive, and neuroradiologic changes were examined in community residing subjects with normal aging or Alzheimerapos;s disease (AD). The results revealed significant decrements between GDS stages 2 and 3; 3 and 4; 4 and 5; and 5 and 6 for most behavioral measures. No decrements were noted between GDS stages 1 and 2. Consequently, the subjective complaints of cognitive decrement, which characterize GDS 2 subjects and which commonly accompany aging, do not appear to be accompanied by objective behavioral or cognitive change. Floor effects for most behavioral and cognitive measures occurred by GDS 6, with nearly uniform bottom scores by GDS stage 7. Computerized tomographic (CT) assessments of brain change revealed significant relationships with global severity on the GDS, but few significant consecutive stage decrements were noted. The magnitude of the relationship between CT assessments of brain change and GDS scores was notably less than the magnitude of the relationship noted between various behavioral measures and GDS. Although behavioral and neurcradiologic measures studied did not reveal decrements in the GDS 2 subjects in comparison with age‐matched GDS 1 subjects who do not have subjective decrements, previous studies of a neuroimmunologic measure (brain reactive antibody levels) do appear to have indicated significant differences between these groups. Consequently, there is some current preliminary evidence for the hypothesis of a physiologic substrate for the subjective deficits characteristic of the GDS 2 stage, as well as clear‐cut behavioral data distinguishing each of the subsequent GDS stages of agi
ISSN:0272-4391
DOI:10.1002/ddr.430150203
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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3. |
Current hypotheses of Alzheimer disease neuropathology and dementia |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 115-121
H. M. Wisniewski,
G. S. Merz,
A. Rabe,
M. Barcikowska,
R. C. Moretz,
E. A. Devine‐Gage,
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摘要:
AbstractImmunology and biochemical studies of paired helical filaments (PHF) revealed the presence of the following proteins: (1) phosphorylated tau, (2) ubiquitin, and (3) neurofilament peptides. Quantitative biochemical studies of the PHF peptides are in progress, and as yet it is not known which of the above proteins or possibly, a novel protein is the initiator and major constitutent of PHF. The peptide‐forming amyloid fibers in the meninges, brain vessels, and neuritic plaques are a product of a host gene localized on chromosome 21. The reason for the formation of the amyloid fibers in normal aged people and in Alzheimer disease is unknown. However, in Down syndrome, it may be a result of a gene dose effect. Imbalance between the production of the amyloid fiber precursor protein and the ability to degrade it may also be the result of gene mutation of the amyloid peptide‐producing cell or a result of an enzyme defect or deficiency of the amyloidogenic peptide processor ce
ISSN:0272-4391
DOI:10.1002/ddr.430150204
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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4. |
Human cerebral amyloidosis |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 123-128
Blas Frangione,
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摘要:
AbstractTwo types of familial cerebral amyloid angiopathy or hereditary cerebral hemorrhage with amyloidosis (HCHWA) have been described: the Icelandic type (HCHWA‐I) and the Dutch type (HCHWA‐D). Both are autosomal‐dominant forms of amyloidosis restricted to the small vasculature of the brain and are clinically characterized by recurrent strokes leading to an early death. In spite of their clinico‐pathological similarities, the amyloid fibrils are structurally different. In the case of HCHWA‐I, the amyloid protein is a degradation product of Cystatin C, a normal serum protein and an inhibitor of cysteine proteases. On the other hand, the amyloid protein in HCHWA‐D has been shown to be related to Alzheimerapos;s disease β‐protein, and preliminary observations indicate that similar amyloid subunits are present in sporadic cerebral amyloid angiopathy and asymptomatic elderly people with amyloidosis. The processing of the β‐protein precursor in different cell types may account for the heterogeneous pattern of clinical manifestations and amyloid deposition in this group of disorders, which we designate “beta
ISSN:0272-4391
DOI:10.1002/ddr.430150205
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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5. |
Structural and functional relationships between the immune and central nervous systems in Alzheimer's disease |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 129-142
Gerald P. Kozlowski,
Gajanan Nilaver,
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摘要:
AbstractAn intact blood–brain barrier (BBB) is a prerequisite to maintaining functional compartmentalization between the neural and immune systems. Only small amounts of immunoglobulins access the internal milieu of the brain, probably via so‐called “functional leaks” existing in the region of the circumventricular organs. However, with aging and disease, globular and other proteins can be found within the cerebrospinal fluid (CSF) because of disruption of perhaps both the BBB and the blood–CSF barrier. There is an increase of lgG, IgA, albumin, and prealbumin in CSF of patients with Alzheimerapos;s disease. The presence of these proteins is taken to be pathognomonic for neuronal impairment, and they are believed to be associated with the amyloid deposits of senile plaques. Our studies have shown that albumins may occur naturally in some CNS neurons. Immunocytochemical studies with antibodies to rat serum albumin have shown the uptake of this serum protein by nerve endings with retrograde transport to perikarya of their cells of origin. Likewise, we have also shown than an endogenous albuminoid substance occurs in arcuate nucleus neurons of the hypothalamus that immunoreact with antibodies to bovine serum albumin. The arcuate nucleus neurons are neurosecretory and have neurohemal endings in contact with blood vessels of the hypothalamohypophysial vasculature. These neurohemal contacts are capable of taking up albumins from the blood for retrograde transport. We, therefore, hypothesize that immunoglobulins may be similarly incorporated by neurons having neurohemal contacts and access the CNS in this and several other ways. We have localized endogenous gammaglobulins in brains of both immunized and nonimmunized rabbits with antisera against rabbit lgG generated in sheep, goat, and mouse. However, serum proteins are also found in neurons without neurohemal contacts. Taken together, albumins, globulins, and other substances may reach the interior milieu of the CNS via: (1) endothelial transcytosis, (2) neurohemal contacts whereby neurons take up blood‐borne substances and retrogradely transport them to their perikarya, (3) circumventricular organs (inter‐ and intraependymal transport), (4) functional leaks at the interface of the circumventricular organs and the brain, (5) a nose–brain pathway, (6) a meningeal pathway, and (7) transsynaptic transport, i.e., substances passed from a neurohemal cell to other con
ISSN:0272-4391
DOI:10.1002/ddr.430150206
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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6. |
Autoimmunity to cholinergic‐specific antigens of the brain in senile dementia of the Alzheimer's type |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 143-151
Howard Fillit,
P. Foley,
H. F. Bradford,
G. Bucht,
B. Winblad,
B. McEwen,
V. Luine,
J. Hardy,
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摘要:
AbstractSenile dementia is a common and devastating disease of the elderly. The most common type of senile dementia is Alzheimerapos;s type (SDAT). The cause of SDAT is unknown. Considerable evidence indicates that the basal forebrain cholinergic system of the brain is primarily involved in the disease process. The mechanisms which account for this specificity of injury is unknown. Several lines of evidence have suggested that autoimmunity may play a role in SDAT. In particular, the presence of antibrain antibodies in the sera of patients with SDAT has been described. However, their specificity has not been defined. Our hypothesis proposes that cholinergic‐specific autoimmunity might play a role in the immunopathogenesis of SDAT. We previously presented data to suggest that antibrain antibodies in SDAT sera are directed against cholinergic‐specific brain antigens. In the current study, a synaptosomal lysis assay was employed to determine if SDAT sera caused specific complement‐dependent immunolysis of cholinergic synaptosomes. Immunolysis was determined by the release of choline acetyltransferase (ChAT), glutamate decarboxylase (GAD), dopamine‐beta‐hydroxylase (DBH), lactate dehydrogenase (LDH), and the inhibition of high affinity choline uptake. Sera from two (American and Swedish) groups of SDAT patients and controls were pair‐tested in a blinded fashion on a single batch of synaptosomes. The results demonstrated that both groups of SDAT sera caused significant specific immunolysis of cholinergic synaptosomes. ChAT release, LDH release, and inhibition of choline uptake were caused by SDAT sera in the presence of complement, while control sera showed little effect. No effect was noted on GAD or DBH release. These data support the hypothesis that a cholinergic‐specific autoimmune response may play a role in the immunopathogenesis of SDAT. Further studies are needed to define the immunochemistry of the cholinergic‐specific antigens recogniz
ISSN:0272-4391
DOI:10.1002/ddr.430150207
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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7. |
Antibodies recognizing cholinergic neurons and thyroglobuline are found in the cerebrospinal fluid of a subgroup of patients with Alzheimer's disease |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 153-163
Amanda McRae‐Degueurce,
Kenneth Haglid,
Lars Rosengren,
Anders Wallin,
Kaj Blennow,
C.‐G. Gottfries,
Annica Dahlström,
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摘要:
AbstractThe presence of cholinergic neuron specific lgG in the CSF of a subgroup of patients with Alzheimerapos;s disease (AD) was demonstrated by immunocytochemistry. The lgG labeled cholinergic nerve cell bodies in the medial septum of rat brains, perfusion fixed with glutaraldehyde/allyl alcohol to fix small transmitter molecules. Many of the patient CSFs also recognized thyroglobuline in an ELISA assay. Antithyroglobuline furthermore recognized the same cholinergic neurons in the rat brain as the CSF and antiacetylcholine, as did anti‐T3 and anti‐T4. The results indicated that in a subgroup of AD patients autoimmune mechanisms may play a role in the pathogenesis of dementia, and that disturbances in the handling of thyroid hormone in the CNS may be involved in the disease proc
ISSN:0272-4391
DOI:10.1002/ddr.430150208
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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8. |
Alzheimer's “syndrome”: Prognosis of subsets with different etiology and preliminary effects of immunotherapy |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 165-174
H. Hugh Fudenberg,
Vijendra K. Singh,
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摘要:
AbstractBased on our current work, we have found aberrations of both cellular immunity and humoral immunity in patients with Alzheimer's disease (AD), suggesting that the bodyapos;s immune system plays an important role in the etiology and/or pathophysiology of at least one subset of AD (we consider AD as a “syndrome”, not a disease). Depending upon the nature of the immune deficits and patientsapos; responsiveness to appropriate immunomodulate therapy, we have thus far differentiated four subsets of AD patients: one subset with defect of a specific T cell (e.g., membrane flexibility) and response to therapy with pyrrolidone compounds; a second subset with autoantibodies to neuron‐axon filament proteins–these patients show clinical improvement after therapy with dialyzable leucocyte extract (DLE) containing transfer factor (TF); a third subset with antibodies to brain antigens (autoimmune) for which therapy is not yet developed; and a fourth subset with none of the abnormalities mentioned above, probably heterogeneous due to one or another biochemical abnormality. We believe that different therapeutic modalities will be necessary for different subsets, much like the situation with other “diseases” such as anemia and diabetes. Our therapeutic results provide additional evidence that AD is a syndrome, not a single disease. Moreover, the clincal improvement demonstrates that the defective function in AD is not due to death of neuronal cells, but rather atrophy or physiologic
ISSN:0272-4391
DOI:10.1002/ddr.430150209
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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9. |
Complement peptides and neuronal dysfunction in the central nervous system: Specificity of receptor sites for anaphylatoxin C3a activity in the rat hypothalamus |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 175-187
Curtis A. Williams,
Nicole Schupf,
Christopher L. Reilly,
Jolynn Wagner,
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摘要:
AbstractThe research described centers on the possible activities of complement in neural tissues. Activation of the complement cascade will generate the pharmacologically potent anaphylatoxins C3a and C5a, cleavage peptides of C3 and C5, respectively. Their actions depend on a carboxyterminal arginine, and they are inactivated by a carboxypeptidase in serum, yielding the desarginated derivatives C3ai and C5ai. Using well‐characterized eating and drinking responses to focal chemical stimulation of hypothalamic sites in the rat, we have shown that immune complex formation elicits consummatory behaviors which mimic the responses to norepinephrine (NE) and dopamine (DA). We have also shown these effects to be complement dependent. C5a was found to stimulate eating, similar to the effect of NE, and C3a was found to mimic the effect of DA, potentiating NE‐induced eating or carbachol‐induced drinking. C5a has been shown to act presynaptically to modulate endogenous catecholamine function. In this study125‐C3a binding to a refined synaptosome preparation reveals a C3a binding site which is completely inhibited by C3ai. We also show that the psychopharmacological action of C3a is also antagonized by C3ai. These studies demonstrate the presence of anaphylatoxin‐sensitive sites in the perisynaptic membrane systems of the rat CNS. They also suggest that the anaphylatoxins could mediate or contribute to the neuropsychiatric disorders often seen in immune comple
ISSN:0272-4391
DOI:10.1002/ddr.430150210
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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10. |
Uptake of normal immunoglobins by motor neurons in the rat: A study using radioiodinated IgG |
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Drug Development Research,
Volume 15,
Issue 2‐3,
1988,
Page 189-194
Roderic H. Fabian,
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摘要:
AbstractSprague‐Dawley rats were anesthetized and the mystatial vibrissae was injected with 0.3‐120 pmol of125I‐labeled affinity‐purified nonspecific rat IgG with and without additional unlabeled IgG in 50 μL of normal saline. Following a survival of 2 days, the rats were deeply anesthetized and perfused with saline and buffered formalin. The brains were removed and punch sample taken that included the facial nuclei. Uptake of radioiodinated IgG by the facial nucleus was determined by subtracting background activity, which was determined from the facial nucleus punch sample contralateral to the injection, from the ipsilateral facial nucleus. Uptake of radiolabeled IgG established a linear relationship with the amount of radiolabeled IgG injected, and only a very small amount was taken up (0.21 fmol per nmol injected). Addition of unlabeled IgG had no effect on the uptake of radiolabeled IgG. This evidence supports immunohistochemical evidence indicating that nonspecific serum IgG is taken up by motor neurons of the CNS with axons projecting the periphery. An increased understanding of this and other aspects of the relationship between the nervous system and the humoral immune system may provide insight concerning the pathogenesis of certain types of autoimmune nervous system
ISSN:0272-4391
DOI:10.1002/ddr.430150211
出版商:Wiley Subscription Services, Inc., A Wiley Company
年代:1988
数据来源: WILEY
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