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The majority of cases of Alzheimer's disease are sporadic. However, there are also numerous examples of families in which Alzheimer's disease is passed from generation to generation. While the sporadic cases of Alzheimer's disease generally begin only at an advanced age, the familial cases are usually of much earlier onset. Some researchers are returning to familial cases of Alzheimer's disease with renewed interest. The authors describe the occurrence of Alzheimer's disease as an inherited trait in two large Belgian families. In both families, the disorder seems to be passed along as an autosomal dominant trait, although mapping of the gene to a particular chromosome has not yet been accomplished for these two families. (Other research has indicated that the gene is on chromosome 21.) A total of 63 affected patients occurred in the two families, and the majority first developed symptoms of Alzheimer's disease in their thirties. While the age of onset of AD for some family members is not known, an onset as early as 26 years was observed and no onset later than age 45 has been documented. The neuropathological examination of autopsy material from the first family revealed the typical neurofibrillary tangles and senile plaques associated with Alzheimer's disease. Since the second family had a greater frequency of myoclonus and pyramidal signs, there was some suggestion that the syndrome might, in fact, be Gerstmann-Straussler-Scheinker syndrome (GSS). However, neuropathological examination of autopsy specimens from this family as well showed the typical changes of Alzheimer's disease and did not show any of the spongiform changes associated with GSS. Numerous studies of Alzheimer's disease have failed to reveal a clear understanding of the underlying genetics; some authors feel that a strong genetic component is masked simply because many people carrying the putative gene do not live long enough to express it. Conversely, studies on identical twins have demonstrated that a single gene is not sufficient to explain the clinical disease. The authors emphasize that familial Alzheimer's disease provides a unique opportunity and urge that if such families are encountered, they be studied in a careful and reliable way and that blood specimens be obtained for subsequent genetic analysis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Evidence That Β-Amyloid Protein in alzheimer's Disease Is Not Derived by Normal Processing ALZHEIMER'S DISEASE (AD), THE most common form of dementia in the elderly, affects [is greater than] 10% [...]

Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated A[Beta]42 levels and the [Epsilon]4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of A[Beta]42 and A[Beta]40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral A[Beta]42 and A[Beta]40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of A[Beta]42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.

Gerstmann-Straussler-Scheinker (GSS) disease is an inherited degenerative disease of the nervous system. The disease, which appears to be inherited as an autosomal dominant trait, first appears between the fourth and seventh decades of life; dementia progresses gradually and after several years rigidity and bradykinesia (slow movement) set in. Psychosis, depression, and rapid weight loss are common at this stage; death usually follows the onset of rigidity by six months to two years. Occasional sporadic cases are observed, however. Neuropathologic findings include the presence of amyloid plaques in the cerebellum and the cerebral cortex. Amyloid plaques are a common pathological feature of Alzheimer's disease; the plaques observed in GSS disease are somewhat intermediate between those observed in Alzheimer's disease and those seen in the rare South Pacific infectious disease kuru. Immunocytochemical techniques have now been used to confirm the distinction between the plaques observed in GSS and those seen in Alzheimer's disease. Alzheimer's disease amyloid plaques are composed predominantly of a protein subunit called A4, which is also known as beta-protein. Antibodies to A4 protein failed to recognize any component of the plaques in GSS disease. Plaques from diseases such as kuru, Creutzfeldt-Jakob disease, and the animal disease scrapie contain a protein called prion protein, or PrP. Although some investigators feel that PrP is also a component of the so-called prions, or infectious proteins, which are conjectured to cause these diseases, this has not been conclusively verified. Antibodies to PrP, however, were found to recognize components of the amyloid plaques in patients with GSS. While tangled neurofibrils are a common neuropathologic feature of Alzheimer's disease, they are not frequently observed in many cases of GSS. However, among the affected family members in the present study, neurofibrillary tangles were found to be numerous. The results indicate that the neuropathological changes in this disease may vary among different family pedigrees and that the normal spectrum of Gerstmann-Straussler-Scheinker disease includes neurofibrillary tangles as well as amyloid plaques. (Consumer Summary produced by Reliance Medical Information, Inc.)

Previous studies have shown that a minor glycoform of acetylcholinesterase (AChE) is increased in Alzheimer's disease brain and cerebrospinal fluid. This glycoform can be distinguished from other AChE species by its lack of binding to concanavalin A (Con A). In this study, the temporal relationship between AChE glycosylation and Aβ deposition was examined in Tg2576 mice. There was a significant (p < 0.05) difference in AChE glycosylation in Tg2576 mice compared with age-matched background strain control mice at 4 months of age. This difference in glycosylation was also observed in 8- and 12-month-old Tg2576 mice. In contrast, Aβ plaques were only seen in the Tg2576 mice at 12 months of age, and were not detected at 4 and 8 months of age. Soluble human-sequence Aβ was detected as early as 4 months of age in the transgenic mice. The altered AChE glycosylation was due to an increase in a minor AChE isoform, which did not bind Con A, similar to that previously observed to be increased in Alzheimer's disease brain and cerebrospinal fluid. The results demonstrate that in transgenic mice altered AChE glycosylation is associated with very early events in the development of AD-like pathology. The study supports the possibility that glycosylation may also be a useful biomarker of AD. [ABSTRACT FROM AUTHOR]

The accumulation of amyloid plaques and amyloid congophilic angiopathy (ACA) in the brains of affected individuals is one of the main pathological features of Alzheimer's disease. Within these deposits, the βA4 (Aß) polypeptide represents a major component with the C-terminal 39–43 amino acid variants being most abundant. Using a mouse IgG1 MoAb produced by hybridoma βA4[35–43]-95.2 3B9, which reacts with the epitope is defined by the amino acid residues βA438[GVV]40, this study has identified a unique conformation within the carboxyl terminus of human βA4[1–42]. Although the βA438[GVV]40 sequence is present within the C-termini of human βA4[1–40] and βA4[1–43] and the βA4-containing region of human APP, the βA4[35–43]-95.2 3B9 MoAb (designated MoAb 3B9) does not bind these polypeptides, demonstrating a high degree of specificity for the βA438[GVV]40 epitope as presented within the βA4[1–42] sequence. The βA4[1–42] epitope bound by MoAb 3B9 is sensitive to heating (100°C for 5 min) and is denatured by SDS but not by oxidative radio-iodination of βA4 or by adsorption to plastic surfaces or nitrocellulose. The recognition of βA4 plaque deposits and ACA by MoAb 3B9 within formalin-fixed sections of human AD brain demonstrates the potential of these antibodies for investigating the role of the unique βA4[1–42] conformation in the development of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Oxidative stress may have an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and prion diseases. Oxidative damage could result from interactions between highly reactive transition metals such as copper (Cu) and endogenous reducing and/or oxidizing molecules in the brain. One such molecule, homocysteine, a thiol-containing amino acid, has previously been shown to modulate Cu toxicity in HeLa and endothelial cells in vitro. Due to a possible link between hyperhomocysteinemia and AD, we examined whether interaction between homocysteine and Cu could potentiate Cu neurotoxicity. Primary mouse neuronal cultures were treated with homocysteine and either Cu (II), Fe (II or III) or Zn (II). Homocysteine was shown to selectively potentiate toxicity from low micromolar concentrations of Cu. The toxicity of homocysteine/Cu coincubation was dependent on the ability of homocysteine to reduce Cu (II) as reflected by the inhibition of toxicity with the Cu (I)-specific chelator, bathocuproine disulphonate. This was supported by data showing that homocysteine reduced Cu (II) more effectively than cysteine or methionine but did not reduce Fe (III) to Fe (II). Homocysteine also generated high levels of hydrogen peroxide in the presence of Cu (II) and promoted Aβ/Cu-mediated hydrogen peroxide production and neurotoxicity. The potentiation of metal toxicity did not involve excitotoxicity as ionotropic glutamate receptor antagonists had no effect on neurotoxicity. Homocysteine alone also had no effect on neuronal glutathione levels. These studies suggest that increased copper and/or homocysteine levels in the elderly could promote significant oxidant damage to neurons and may represent additional risk factor pathways which conspire to produce AD or related neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

When PC12 cells are deprived of trophic support they undergo apoptosis. We have previously shown that survival of trophic factor-deprived PC12M1 cells can be promoted by activation of the G protein-coupled muscarinic receptors. The mechanism whereby muscarinic receptors inhibit apoptosis is poorly understood. In the present study we investigated this mechanism by examining the effect of muscarinic receptor activation on the serum deprivation-induced activity of key players in apoptosis, the caspases, in PC12M1 cells. The results showed that m1 muscarinic activation inhibits caspase activity induced by serum deprivation. This effect appeared to be caused by the prevention of activation of caspases such as caspase-2 and caspase-3, and not by the inhibition of existing activity. Muscarinic receptor activation also stimulated the mitogen-activated protein kinase/extracellular signalingregulated kinase (MAPK/ERK) and phosphoinositide (PI) 3kinase signaling pathways. The PI 3-kinase pathway inhibitors wortmannin and LY294002, as well as the MAPK/ERK pathway PD98059 inhibitor, did not however suppress the inhibitory effect of the muscarinic receptors on caspase activity. The results therefore suggested that the muscarinic survival effect is mediated by a pathway that leads to caspase inhibition by MAPK/ER K- and PI 3-kinase-independent signaling cascades. [ABSTRACT FROM AUTHOR]

Peptide aldehyde inhibitors of the chymotrypsin-like activity of the proteasome (CLIP) such as N-acetyl-Leu-Leu-Nle-H (or ALLN) have been shown previously to inhibit the secretion of β-amyloid peptide (Aβ) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on Aβ formation of a much wider range of peptide-based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of β-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress Aβ formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in Aβ formation. [ABSTRACT FROM AUTHOR]

Many studies have shown that breakdown of the amyloid protein precursor (APP) to produce the amyloid protein is an important step in the pathogenic mechanism which causes Alzheimer's disease (AD).  However, little is known about the normal function of APP.  Developmental studies show that APP expression increases during the period of brain development when neurite outgrowth and synaptogenesis is maximal.  APP is expressed highly within growing neurites and in growth cones, and purified APP has been shown to stimulate neurite outgrowth from cells in culture.  Thus APP may regulate neurite outgrowth or synaptogenesis in vivo. APP is actively secreted from many cells, and the C-terminally secreted APP has been shown to associate with components of the extracellular matrix, such as the heparan sulphate proteoglycans (HSPGs).  Two putative heparin-binding domains on APP have been reported.  Binding of HSPGs to an N-terminal heparin-binding domain (HBD-1) stimulates the effect of substrate-bound APP on neurite outgrowth.  In the mature nervous system, APP may play an important role in the regulation of wound repair.  It is highly likely that studies on the normal functions of APP will shed further light on aspects of the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

In the present review, we shall discuss the pros and cons of a possible functional relationship and contribution of the APP family members (APP, APLP1 and APLP2) to the development of Alzheimer's disease: (1) APP, APLP1 and APLP2 are highly homologous proteins with similar protein domain organization. (2) All APP family proteins have been found to be aggregated in typical Alzheimer's disease lesions. (3) Several other proteins have been implied to provide a functional link among the APP-related proteins. In normal adult brain APP, APLP1 and APLP2 are involved in synaptic processes important for memory function. We hypothesize that the functional loss of members of the APP family contributes to the gradual cognitive decline in Alzheimer's disease patients. [ABSTRACT FROM AUTHOR]

This study compared clinical diagnosis of dementia derived from medical records and a retrospective version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) against the criterion of neuropathology. Subjects comprised 50 consecutive patients who died in a geriatric hospital in Melbourne and underwent necropsy. All informants were seen within 3.5 years of death. Discordance between clinical and pathological diagnosis occurred in seven (14%) cases, The IQCODE scores for the group with a clinical diagnosis of Alzheimer's disease (mean ± SD) were 4.28 ± 0.78 and were significantly different from the non-demented group, 3.39 ± 0.51, p < 0.001. Similarly, IQCODE scores were significantly different between the groups with and without a pathologic diagnosis of AIzheimer's disease, 4.21 ± 0.70 and 3.51 ± 0.79 respectively, p < 0.01. Using immunohistochemical techniques instead of conventional methods to make a diagnosis of Alzheimer's disease, there were significant differences in IQCODE scores between the Alzheimer's group. 4.13 ± 0.83, and the group with normal neuropathology. 3.45 ± 0.54, p < 0.01, These data support the conclusion that when used retrospectively, the IQCODE is a valid screening test for dementia using neuropathological diagnosis as the criterion. [ABSTRACT FROM AUTHOR]