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The molecular genetic strategies aimed at isolating and characterizing the defective gene(s) in familial Alzheimer's disease, the inherent limitations of the techniques and recent progress in the field are reviewed. Three independent groups have found an apparent linkage to chromosome 21 but two other groups have not, suggesting that familial Alzheimer's disease may be etiologically heterogeneous.
Genetic linkage analysis requires the identification and documentation of large families with many affected members present, preferably in more than one generation. The IMAGE Project has been establishing a population- based Alzheimer disease (AD) registry in the Saguenay - Lac-Saint-Jean region of the Province of Quebec. The population of this region has a well-documented ancestry, with reliable genealogical records (since 1842) computerized by SORER We have recently begun to investigate the pedigrees of selected probands (definite, probable and possible) from the IMAGE registry in order to identify informative pedigrees for genetic linkage analysis. Interviews were carried out with close relatives of the probands (at least one informant per sibship) to identify secondary AD cases. The questionnaires used pertain to the accuracy of genealogical records, to family medical history and to a retrospective diagnosis of AD for people with cognitive deficits. By these means, we have documented a large extended pedigree in which a total of 15 individuals with cognitive deficits were ascertained over three generations. Of these cases, 7 are still living and there is autopsy confirmation in another one. Computer simulations using the program SIMLINK revealed that this is a potentially informative family for linkage analysis. Horizontal extension of the pedigree to second cousins of the proband is now being carried out. This will render the family IMAGE/1 even more informative in genetic linkage analysis studies.
We review the evidence for altered gene expression in Alzheimer's disease brain and identify alternative molecular approaches for isolating additional novel markers. One marker, pADHC-9, was isolated from a human hippocampal cDNA library by differential screening with AD and control cDNA probes. This clone hybridizes to a 2 Kb RNA which is increased 2 fold in AD hippocampus. The deduced amino acid sequence of pADHC-9 codes for a 52 kDAL protein similar to a testicular sulfated glycoprotein secreted by rat Sertoli cells. The normal function of this protein in brain and whether that function is altered in Alzheimer's disease is unknown.
There is extensive evidence for decrements of gene expression in AD, at several levels in the process. There is also evidence for increments of expression of some genes. Message for the amyloid precursor protein (APP), for example, is elevated in surviving neurons of certain subcortical populations in AD. We evaluated expression of message for APP as well as for certain neuronal and glial cytoskeletal proteins in the cortex of six cases of AD. Neuronal mRNAs, including that for APP, were significantly decreased when compared with control cortex, whereas the glial mRNA was increased. We have projected studies to determine the evolution of these mRNA decrements in Alzheimer-type degeneration. The rationale for these studies and preliminary findings are discussed.
The pathological changes that occur in Alzheimer disease (AD) brain lead to a large loss of various classes of neurons and the production of novel proteinaceous elements such as neuritic plaques and neurofibrillary tangles. For the neuronal loss to occur and these elements to arise, there must be a disturbance in the expression or regulation of genes that code for proteins required for normal cell maintenance, or perhaps even for the expression of genes unique to AD. We describe the construction of a cDNA library from the human substantia innominata and strategies for isolating genes that are expressed differentially between brain regions and which may be affected by AD. Some of the results obtained using these strategies and a preliminary description of a novel brain specific mRNA of 15.5kb, whose expression is increased in AD affected temporal cortex, are presented.
Application of molecular biological techniques and sensitive elemental analysis have produced new evidence implicating aluminum as an important factor in down regulation of neuronal protein metabolism. Aluminum in Alzheimer's disease may act by electrostatically crosslinking proteins, particularly the methionine containing histone Hl°, and DNA. The consequence of such crosslinking is reduced transcription of at least one neuron specific gene, the low molecular weight component of neurofilaments. In the superior temporal gyrus in Alzheimer's disease, down regulation of this gene occurs in approximately 86% of surviving neurons and, therefore, aluminum must be considered as having an active role in the pathogenesis. Epidemiological studies are reviewed that independently support the hypothesis that environmental aluminum is a significant risk factor. Preliminary evidence also suggests that a disorder in phosphorylation may be an important initiating factor.
We have attempted to verify the presence of increased aluminum (Al) levels in Alzheimer's disease (AD) brains by energy dispersive X-ray microanalysis (EDX) and flameless atomic absorption spectrophotometry (AAS). Tissue from seven AD brains, mounted on carbon polymerized coverslips, were stained with Congored or treated immunohistochemically to allow optical localization of AD-associated lesions during EDX. Despite a demonstrated sensitivity of 20-25 ppm, we were unable to detect Al in either plaque cores or neurons containing neurofibrillary tangles. For AAS, wet weight samples (ranging from 48-144 mg) from six of the seven AD brains and four controls were selected from regions similar to those studied under EDX, i.e., Brodmann areas 9, 11, 28, 46, 47, and the hippocampus. The tissue surrounding each sample site was sectioned and stained for thioflavin S. Both controls and AD samples revealed similar levels of Al ranging from undetectable to 1.80 ng/mg wet wt. (mean AD: 0.28 ± 0.39 (SD), control: 0.54 ± 0.58 (SD)), independent of degree of histopathology or age of the case. We conclude that the combined strengths of these two techniques on similar tissue specimens demonstrate that abnormal Al levels are not required to produce the histologic findings of AD and that this element may not accumulate in the aging brain. It is unlikely, therefore, that Al is essential in the etiology of pathogenesis of plaques and tangles in AD. Al's role as a primary or secondarily associated event, when present, needs further delineation.
A review of biochemical findings is presented which support the idea that Alzheimer's disease represents a condition for which tetrahydroaminoacridine (tacrine) may have a beneficial effect. There is evidence that clinical and histopathologic hallmarks of the disease relate to cholinergic and serotonergic dysfunction, with less obvious abnormalities in other neurotransmitters (aspartate, dopamine, gamma-aminobutyrate, glutamate, noradrenaline and somatostatin). Clincially relevant concentrations of tacrine may ameliorate the above presynaptic deficits without producing harmful (neurotoxic) effects of aspartate and glutamate. The disease seems to be associated with an early and clinically relevant degeneration of some neurons with cortical perikarya that release these amino acid transmitters. Studies are now required on the effect of tacrine on postulated harmful peptide-bond hydrolase activity within and around such cells.
Large pyramidal neurons of rat and human neocortex stain immunohistochemically for phosphate-activated glutaminase (PAG). In a limited number of postmortem brains, we find large reductions in cortical PAG activity in Alzheimer's disease (AD). This finding is consistent with histological evidence that pyramidal neurons are affected in AD. The reductions are greater than those found in the same samples in choline acetyltransferase (ChAT) but the possible deleterious effects of coma and similar premortem factors on human PAG activity have yet to be assessed. The activity of (β-glucuronidase, a lysosomal enzyme which occurs in reactive astrocytes, is elevated in the same samples. Positron emission tomography (PET) studies, using 18F-fluorodeoxyglucose (FDG), have demonstrated significant deficiencies in glucose metabolism in the cortex in AD, with the parietal, temporal and some frontal areas being particularly affected. We found in serial scans of 13 AD cases, including one relatively young (44-46 year old) familial case, an exacerbation of the defect over time in most cases. We have found a negative correlation between the regional metabolic rates for glucose (LCMR(s)) measured premortem and the (β-glucuronidase activities measured postmortem on a few AD cases that have come to autopsy. The correlations between LCMR(s) and PAG and ChAT activities tend to be positive. The results are consistent with previous suggestions that decreased LCMR(s) in AD reflect local neuronal loss and gliosis.
Involvement of the immune system in the pathogenesis of Alzheimer's disease was demonstrated in two ways: by the attachment of complement proteins to diseased tissue, and by the activation of cells associated with the immune system. Alzheimer brain tissue was stained immunohistochemically by antibodies to components of the classical, but not the alternative, complement pathway. Antibodies to Clq, C3d, and C4d stained senile plaques, dystrophic neurites, neuropil threads and some tangled neurons. Antibodies to a neoantigenic site on the C5b-9 membrane attack complex stained dystrophic neurites and many tangled neurons, but not senile plaques. Antibodies to Factor P and fraction Bb of Factor B, which are specific for the alternative complement pathway, did not stain Alzheimer brain tissue. The cellular immune response was evaluated by the presence of reactive microglia and by the infiltration of small numbers of T-cells into diseased brain tissue. Reactive microglia were identified by antibodies to HLA-DR, a class II major histocompatibility complex glycoprotein, and by enhanced staining with antibodies to leukocyte common antigen and the FC7RI and FcyRII receptors. T-cells were identified by antibodies to leukocyte common antigen, as well as the CD4 and CD8 surface proteins. Double immunostaining with antibodies to GFAP and MHC class I or class II antigens established that astrocytes, which are GFAP positive, do not express MHC antigens in Alzheimer's disease. Endothelial cells express MHC class I antigens while reactive microglia and some leukocytes express class II antigen.
A blind study showing that serum from patients with Alzheimer's disease causes immunolysis of mammalian brain synaptosomes is reported. Control, aged-matched, sera were largely without effect. The immunolysis was directed mainly against cholinergic synaptosomes. The data support the hypothesis that autoimmune mechanisms may operate in the pathogenesis of Alzheimer's disease.
Three-dimensional reconstruction and ultrastructural studies of classical plaques from the cortex of patients with Alzheimer's disease showed that microglial cells of the plaques are the amyloid-forming cells. The amyloid star of the single plaque represents the product of five or six microglial cells covering about 80% of the amyloid star surface. The amyloid fibers appear to be formed within altered cisterns of the endoplasmic reticulum. Distended cisterns form channels filled with amyloid fibers. Numerous vesicles derived from the Golgi apparatus appear to be attached to or fused with the amyloid-filled channels. Reconstruction of the amyloid star and the microglia cell pole that forms the amyloid star reveals three different zones of distribution of cytoplasmic organelles and amyloid deposits. The peripheral zone comprises channels filled with loosely packed amyloid fibers arranged in a parallel manner. The transient zone consists of a mixture of fusing amyloid channels and products of disintegration of cytoplasmic pockets, dense bodies and fragments of cellular membranes. The core of the amyloid star is composed of condensed, densely packed amyloid fibers that are free of cellular debris. Formation of the three zones supports the idea that the microglia/macrophages are not phagocytes but instead are the cells manufacturing the amyloid fibers.
Since the discovery of a significant depletion of acetylcholine in discrete areas of the brain of patients affected by Alzheimer's disease, attempts at symptomatic therapy have concentrated on acetylcholine supplementation, an approach that is based upon the efficacy of dopaminergic supplementation therapy for Parkinson's disease. Choline, then lecithin, used orally, failed to improve symptoms but the hypothesis that long-term choline supplementation might stabilize the course of Alzheimer's disease remains to be tested. Nerve growth factor may also offer that possibility. Bethanechol administered intracerebroventricularly did not help when a fixed dose was used but individual titration of more selective muscarinic agonists may prove more effective. In this article we report that tetrahydroaminoacridine (THA), given together with highly concentrated lecithin, appears to bring improvement in cognition and in functional autonomy using the Mini Mental State and the Rapid Disability Rating Scale-2 respectively, without change in behavior as reflected by the Behave-AD. Double-blind cross-over studies are in progress to establish its efficacy. Improvement in study design and means of assessment of cognition, functional autonomy and behavior have been made possible by these drug trials.
We argue against the dominant status assigned to conventional microscopy in the categorization of disorders such as Alzheimer's disease, Parkinson's disease and ALS. As an example we criticize the emphasis that has been placed on correlating the presence of Lewy bodies with the diagnosis of Parkinson's disease. In essence, we submit that Parkinson's disease can exist without Lewy bodies, and Lewy bodies can exist without Parkinson's disease. Nevertheless, we consider that the newer techniques available to histology have led to an important concept that constitutes a shared feature for Alzheimer's disease. Parkinson's disease and ALS; they are all characterized by the deposition of cytoskeletal debris in tissue, so they may perhaps be collectively termed the “Cytoskeletal Disorders”.