Beta-amyloid protein: recent progress in basic research and therapeutic approaches]

Deposition of amyloid beta protein (A beta) as senile plaques or cerebrovascular amyloid characterizes the brains of patients with Alzheimer's disease (AD). A beta are composed of 40-42 amino acids that are proteolytically produced from its precursor beta APP. We have shown that the deposition of A beta ending at the 42nd residue (A beta 42) is one of the earliest pathological changes in AD brains. Genetic and cell biological evidence strongly suggests that mutations in beta APP or presenilin (PS) 1 and 2 genes cause AD through increase in production of A beta 42. Recently. PS1 and PS2 are shown to be the catalytic subunits of gamma-secretase that cleaves the intramembrane segments of beta APP and Notch. beta-amyloid hypothesis that emphasizes the primacy of A beta in the pathogenesis of AD is currently being verified by the new experimental therapeutic approaches, e.g., A beta vaccine therapy or administration of inhibitors of beta- or gamma-secretases.     

Intracellular APP processing and A beta production in Alzheimer disease.

Senile plaques composed of A beta peptides are a histopathological hallmark of Alzheimer disease (AD). A role for A beta in the etiology of AD has been argued from analysis of mutations associated with a subset of early-onset familial AD (FAD). Expression of autosomal dominant mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) in affected patients, cultured cells, or transgenic mice leads to increased production of total A beta or increased production of A beta ending at residue 42 (A beta42). Since A beta42 is the more amyloidogenic and toxic species in vitro and is the major component of amyloid senile plaques in vivo, overproduction of this peptide may play a crucial role in the pathogenesis of AD. Thus, an understanding of the production of A beta within the cell in normal and pathological conditions is critical to understanding early events in AD. Studies in cell culture have established that processing of APP to form A beta can occur at multiple locations within the cell and leads to the production of 2 pools of A beta: a secreted pool composed predominantly of A beta40 and a nonsecreted, intracellular pool composed preferentially of more amyloidogenic A beta42. The purpose of this review is to provide a summary of our current understanding of APP processing in the generation of the secreted and intracellular pools of A beta and to propose a model linking the intracellular pool to the formation of extracellular plaques and neuronal pathology in AD.     

Genetic aspects of amyloid beta-protein fibrillogenesis in Alzheimer's disease

Although deposition of aggregated amyloid beta-protein (Abeta) in human brain is a fundamental pathological event in the development of Alzheimer's disease (AD), our knowledge of the molecular mechanisms underlying the initiation of Abeta fibril formation remains still very incomplete. Recent data indicate that genetic factors have a direct effect on Abeta fibrillogenesis. Most of pathogenic mutations identified in genes responsible for familial AD (FAD) affect activities of alpha-, beta, and gamma-secretases during amyloid precursor protein (APP) processing leading to a significant increase in the Abeta42/Abeta40 concentration ratio. The enhanced anabolism of Abeta may lead to its deposition. Recently, it was shown that the two main alloforms of Abeta have distinct biological activity and behaviour at the earliest stage of assembly. In vitro studies showed that Abeta42 monomers, but not Abeta40, form initial and minimal structures (pentamer/hexamer units called paranuclei), which can oligomerise to larger forms. This finding may explain the particularly strong association of Abeta42 with AD. We have reviewed molecular effects of APP and Presenilin mutations responsible for FAD in both Abeta metabolism and formation of Abeta fibril.     

Age-related progressive synaptic dysfunction: the critical role of presenilin 1

Mutations in presenilin 1 gene (PS1) account for the majority of early-onset familial Alzheimer's disease (FAD) cases. The disease is characterized by intracellular neurofibrillary tangles and extracellular amyloid fibrils composed of amyloid beta peptides (Abeta). Two successive cleavages are necessary to free the Abeta peptide from the amyloid precursor protein (APP). Gamma-secretase catalyzes the final cleavage of APP to generate Abeta peptides. PS1 is a catalytic subunit of gamma-secretase and is also involved in the cleavage of many membrane proteins. PS1 also has functional interactions with many other proteins. The use of animal models of AD has initiated the deciphering of these molecular pathways and mechanisms. Transgenic mouse models are useful to study the features of FAD and to investigate the nature of the neural-tissue changes of the disease and their evolution during aging. When expressed alone, mutations in human PS1 do not induce any detectable lesions, although they do increase Abeta peptides. This absence has led to the criticism that PS1 mouse models are not valuable for the study of AD. In this review we present how studies using PS1 transgenic mice have raised new questions related to pathological mechanisms of AD and are useful models for the study of (1) progressive cognitive decline, (2) early-occurring synaptic dysfunction, and (3) mechanisms other than amyloidogenesis that can be involved in disease pathogenesis.     

Neuropathological Characterization of Mutant Amyloid Precursor Protein Yeast Artificial Chromosome Transgenic Mice

Mutations in the amyloid precursor protein (APP) gene result in elevated production and deposition of the 42 amino acid beta-amyloid (Abeta1-42) peptide and early-onset Alzheimer's disease (AD). To accurately examine the effect of the APP FAD mutations in vivo, we introduced yeast artificial chromosomes (YACs) containing the entire genomic copy of human APP harboring FAD mutations into transgenic mice. Our current results demonstrate that mutant APP YAC transgenic mice exhibit many features characteristic of human AD, including regional deposition of Abeta with preferential deposition of Abeta1-42, extensive neuritic abnormalities as evidenced by staining with APP, ubiquitin, neurofilament, and hyperphosphorylated tau antibodies, increased markers of inflammation, and the overlapping deposition of Abeta with apolipoproteins E and J. Our results also suggest that APP YAC transgenic mice possess unique pathological attributes when compared to other transgenic mouse models of AD that may reflect the experimental design of each model.     

Alzheimer's disease pathogenesis and therapeutic interventions.

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system associated with progressive cognitive and memory loss. Molecular hallmarks of the disease are characterized by extracellular deposition of the amyloid beta peptide (Abeta) in senile plaques, the appearance of intracellular neurofibrillary tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus and other areas of brain essential for cognitive and memory functions. Abeta deposition causes neuronal death via a number of possible mechanisms including oxidative stress, excitotoxicity, energy depletion, inflammation and apoptosis. Despite their multifactorial etiopathogenesis, genetics plays a primary role in progression of disease. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). Plaques are formed mostly from the deposition of Abeta, a peptide derived from APP. The main factors responsible for Abeta formation are mutation of APP or PS1 and PS2 genes or ApoE gene. All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. In addition to genetic influences on amyloid plaque and intracellular tangle formation, environmental factors (e.g., cytokines, neurotoxins, etc.) may also play important role in the development and progression of AD. A direct understanding of the molecular mechanism of protein aggregation and its effects on neuronal cell death could open new therapeutic approaches. Some of the therapeutic approaches that have progressed to the clinical arena are the use of acetylcholinesterase inhibitors, nerve growth factors, nonsteroidal inflammatory drugs, estrogen and the compounds such as antioxidants, neuronal calcium channel blockers or antiapoptotic agents. Inhibition of secretase activity and blocking the formation of beta-amyloid oligomers and fibrils which may inhibit fibrilization and fibrilization-dependent neurotoxicity are the most promising therapeutic strategy against the accumulation of beta-amyloid fibrils associated with AD. Furthermore, development of immunotherapy could be an evolving promising therapeutic approach for the treatment of AD.     

Human wild presenilin-1 mimics the effect of the mutant presenilin-1 on the processing of Alzheimer's amyloid precursor protein in PC12D cells

Most familial early-onset Alzheimer's disease (FAD) is caused by mutations in the presenilin-1 (PS1) gene. Abeta 42 is derived from amyloid precursor protein (APP) and increased concentrations are widely believed to be a pathological hallmark of abnormal PS function. Thus, the interaction between PS1 and APP is central to the molecular mechanism of AD. To examine the effect of wild-type human PS1 on rat APP metabolism, we made several PC12D cell lines that expressed human wild or mutant PS1, and analyzed the processing of endogenous rat APP and the intracellular gamma-secretase activity. We found the ratio of Abeta 42/Abeta 40 increased in PC12D cells expressing wild-type human PS1. These changes were identical to those found in PC12D cells expressing human PS1 bearing the A260V mutation. These results suggest that APP metabolism is physiologically regulated by the PS1 and that loss of normal PS1 affects gamma-secretase activity.     

Amyloid precursor protein gene mutations responsible for early-onset autosomal dominant Alzheimer's disease

According to the "amyloid cascade hypothesis", the accumulation of A beta peptides in the brain is a primary event in the pathogenesis of Alzheimer's disease (AD). Other pathological features (neurofibrillary tangles, neuronal damage and cell death) are regarded as secondary. One of the strong pieces of evidence supporting this hypothesis was the identification of over 20 pathogenic mutations within the APP gene responsible for familial EOAD. The APP mutations are located close to the sites recognised by the alpha-, beta- and gamma-secretases. The mutations affect the APP processing, causing overproduction of A beta42 peptide. The imbalance between A beta production and A beta clearance releases a cascade of subsequent cellular processes leading to AD. In this paper, all APP mutations have been summarised and their molecular effects on the APP metabolism have been discussed.     

Deposition of mouse amyloid beta in human APP/PS1 double and single AD model transgenic mice

The deposition of amyloid beta (Abeta) peptides and neurofibrillary tangles are the two characteristic pathological features of Alzheimer's disease (AD). To investigate the relation between amyloid precursor protein (APP) production, amyloid beta deposition and the type of Abeta in deposits, i.e., human and/or mouse, we performed a histopathological analysis, using mouse and human specific antibodies, of the neocortex and hippocampus in 6, 12 and 19 months old APP/PS1 double and APP and PS1 single transgenic mice. There was a significant correlation between the human amyloid beta deposits and the intrinsic rodent amyloid beta deposits, that is, all plaques contained both human and mouse Abeta, and the diffuse amyloid beta deposits also colocalized human and mouse Abeta. Furthermore, some blood vessels (mainly leptomeningeal vessels) show labeling with human Abeta, and most of these vessels also label with mouse Abeta. Our findings demonstrate that the human amyloid deposits in APP/PS1 transgenic mice are closely associated with mouse Abeta, however, they do not precisely overlap. For instance, the core of plaques consists of primarily human Abeta, whereas the rim of the plaque contains both human and mouse amyloid beta, similarly, human and mouse Abeta are differentially localized in the blood vessel wall. Finally, as early as amyloid beta deposits can be detected, they show the presence of both human and mouse Abeta. Together, these data indicate that mouse Abeta is formed and deposited in significant amounts in the AD mouse brain and that it is deposited together with the human Abeta.     

Molecular genetics of Alzheimer's disease.

Application of genetic paradigms to Alzheimer's disease (AD) has led to confirmation that genetic factors play a role in this disease. Additionally, researchers now understand that AD is genetically heterogeneous and that some genetic isoforms appear to have similar or related biochemical consequences. Genetic epidemiologic studies indicate that first-degree relatives of AD probands have an age-dependent risk for AD approximately equal to 38% by age 90 years (range 10% to 50%). This incidence strongly suggests that transmission may be more complicated than a simple autosomal dominant trait. Nevertheless, a small proportion of AD cases with unequivocal autosomal dominant transmission have been identified. Studies of these autosomal dominant familial AD (FAD) pedigrees have thus far identified four distinct FAD genes. The beta-amyloid precursor protein (beta APP) gene (on chromosome 21), the presenilin 1 (PS1) gene (on chromosome 14), and the presenilin 2 (PS2) gene (on chromosome 1) gene are all associated with early-onset AD. Missense mutations in these genes cause abnormal beta APP processing with resultant overproduction of A beta 42 peptides. In addition, the epsilon 4 allele of apolipoprotein E (APOE) is associated with a increased risk for late-onset AD. Although attempts to develop symptomatic treatments based on neurotransmitter replacement continue, some laboratories are attempting to design treatments that will modulate production or disposition of A beta peptides.     

A novel presenilin-1 mutation: Increased β-amyloid and neurofibrillary changes

The prevalence of known mutations in presenilin genes (PS1 and PS2) causing early-onset familial Alzheimer's disease (FAD) was assessed in a population of 98 singleton early-onset AD cases, 29 early-onset FAD cases, and 15 late-onset FAD cases. None of the cases tested positive for the eight mutations initially reported, and none of these mutations were observed in 60 age-matched controls. A novel mutation (R269H) in PS1 was found in a single case of early-onset AD but not in any other AD or control case. Thus, the PS mutations tested are quite rare in early-onset AD. Amyloid β protein (Aβ) deposition was investigated in the temporal cortex of the R269H mutation case using end-specific monoclonal antibodies to detect the presence of Aβ_x?40 and Aβ_x?42 subspecies. Stereologically unbiased tangle and neuropil thread counts were obtained from the same region. R269H PS1 mutation was associated with early age of dementia onset, higher amounts of total Aβ and Aβ_x?42, and increased neuronal cytoskeletal changes. Thus, if the changes observed on this case prove to be typical of PS1 mutations, PS1 mutations may impact both amyloid deposition and neurofibrillary pathology.     

Beta- and gamma-secretases]

Deposition of amyloid beta peptides (Abeta) as amyloid deposits characterizes the brains of patients with Alzheimer's disease (AD). Mutations in presenilin genes linked to familial AD (FAD) have been shown to increase production of Abeta42, an initially and predominantly depositing Abeta species in all types of AD. PS has been shown to serve as the catalytic center for the gamma-secretase cleavage of a subset of single-pass membrane proteins including beta-amyloid precursor protein and Notch. gamma-Secretase inhibitors, including gamma42-selective inhibitors like NSAIDs, are emerging therapeutic agents for AD. Also, an establishment of a method to monitor the progression of AD using imaging and biochemical surrogate markers would be vital to the evaluation of the effects of disease-modifying drugs for AD. In this regard, a large-scale observation study, like the AD neuroimaging initiative (ADNI), should be conducted in Japan.     

Genes and mechanisms involved in β-amyloid generation and Alzheimer’s disease

Alzheimer's disease is characterized by the invariable accumulation of senile plaques that are predominantly composed of amyloid beta-peptide (Abeta). Abeta is generated by proteolytic processing of the beta-amyloid precursor protein (betaAPP) involving the combined action of beta- and gamma-secretase. Cleavage within the Abeta domain by alpha-secretase prevents Abeta generation. In some very rare cases of familial AD (FAD), mutations have been identified within the betaAPP gene. These mutations are located close to or at the cleavage sites of the secretases and pathologically effect betaAPP processing by increasing Abeta production, specifically its highly amyloidogenic 42 amino acid variant (Abeta42). Most of the mutations associated with FAD have been identified in the two presenilin (PS) genes, particularly the PS1 gene. Like the mutations identified within the betaAPP gene, mutations in PS1 and PS2 cause the increased generation of Abeta42. PS1 has been shown to be functionally involved in Notch signaling, a key process in cellular differentation, and in betaAPP processing. A gene knock out of PS1 in mice leads to an embryonic lethal phenotype similar to that of mice lacking Notch. In addition, absence of PS1 results in reduced gamma-secretase cleavage and leads to an accumulation of betaAPP C-terminal fragments and decreased amounts of Abeta. Recent work may suggest that PS1 could be the gamma-secretase itself, exhibiting the properties of a novel aspartyl protease. Mutagenesis of either of two highly conserved intramembraneous aspartate residues of PS1 leads to reduced Abeta production as observed in the PS1 knockout. A corresponding mutation in PS2 interfered with betaAPP processing and Notch signaling suggesting a functional redundancy of both presenilins. In this issue, some of the recent work on the molecular mechanisms involved in Alzheimer's disease (AD) as well as novel diagnostic approaches and risk factors for AD will be discussed. In the first article, we like to give an overview on mechanisms involved in the proteolytic generation of Amyloid beta-peptide (Abeta), the major pathological player of this devastating disease. In the second part of this article recent results will be described, which demonstrate an unexpected biological and pathological function of an AD associated gene.     

LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease

LR11 is an ApoE receptor that is enriched in the brain. We have shown that LR11 is markedly downregulated in patients with sporadic Alzheimer disease (AD). This finding led us to explore whether reduced LR11 expression reflects a primary mechanism of disease or merely a secondary consequence of other AD-associated changes. Therefore, LR11 expression was assessed in a transgenic mouse model of AD and familial AD (FAD) brains. Immunohistochemistry and immunoblotting of LR11 in PS1/APP transgenic and wild-type mice indicated that LR11 levels are not affected by genotype or accumulation of amyloid pathology. LR11 expression was also evaluated based on immunoblotting and LR11 immunostaining intensity in human frontal cortex in controls, sporadic AD, and FAD, including cases with presenilin-1 (PS1) and presenilin-2 (PS2) mutations. Although LR11 was reduced in sporadic AD, there was no difference in protein level or staining intensity between control and FAD cases. The finding that LR11 expression is unaffected in both a mouse model of AD and autosomal-dominant forms of AD suggests that LR11 is not regulated by amyloid accumulation or other AD neuropathologic changes. We hypothesize that LR11 loss may be specific to sporadic AD and influence amyloid pathology through mechanisms independent of substrate-enzyme interactions regulated by FAD mutations.     

Amyloid precursor protein gene analysis in familial Alzheimer's disease cases: a lack of mutations in exons 16 and 17

The beta-amyloid precursor protein (APP) gene (on chromosome 21), Presenilin 1 (PS1) gene (on chromosome 14) and Presenilin 2 (PS2) gene (on chromosome 1) are responsible for autosomal dominant early-onset Alzheimer's disease (EOAD). Missense mutations in these genes cause abnormal APP processing with subsequent overproduction of amyloidogenic and toxic A beta (42 peptide. A mutational analysis of APP, PS1, and PS2 genes can be used for both symptomatic and presymptomatic genetic testing and counselling in familial Alzheimer's disease (FAD). To contribute to our knowledge on genetic background of Alzheimer's disease in Poland, we screened APP mutations in a sample of familial EOAD cases from Poznan region. We did not find pathogenic mutations within exons 16 and 17 of the APP gene. Our study confirmed that APP gene mutations account only for a very small portion of FAD.     

Enhanced generation of intracellular Aβ42 amyloid peptide by mutation of presenilins PS1 and PS2

The accumulation of amyloid β‐peptide (Aβ) in the brain is a critical pathological process in Alzheimer's disease (AD). Recent studies have implicated intracellular Aβ in neurodegeneration in AD. To investigate the generation of intracellular Aβ, we established human neuroblastoma SH‐SY5Y cells stably expressing wild‐type amyloid precursor protein (APP), Swedish mutant APP, APP plus presenilin 1 (PS1) and presenilin 2 (PS2; wild‐type or familial AD‐associated mutant), and quantified intracellular Aβ40 and Aβ42 in formic acid extracts by sensitive Western blotting. Levels of both intracellular Aβ40 and Aβ42 were 2–3‐fold higher in cells expressing Swedish APP, compared with those expressing wild‐type APP. Intracellular Aβ42/Aβ40 ratios were approximately 0.5 in these cells. These ratios were increased markedly in cells expressing mutant PS1 or PS2 compared with those expressing their wild‐type counterparts, consistent with the observed changes in secreted Aβ42/Aβ40 ratios. High total levels of intracellular Aβ were observed in cells expressing mutant PS2 because of a marked elevation of Aβ42. Immunofluorescence staining additionally revealed more intense Aβ42 immunoreactivity in mutant PS2‐expressing cells than in wild‐type cells, which was partially colocalized with immunoreactivity for the trans‐Golgi network and endosomes. The data collectively indicate that PS mutations promote the accumulation of intracellular Aβ42, which appears to be localized in multiple subcellular compartments.     

AMY plaques in familial AD: comparison with sporadic Alzheimer's disease

OBJECTIVE: To assess AMY expression in familial AD (FAD). BACKGROUND: The discovery of nonbeta-amyloid (Abeta), plaque-like deposits composed of a 100-kd protein (AMY) in sporadic AD (SAD) brains prompted us to determine whether these plaques (AMY plaques) also occur in AD due to mutations of the presenilin-1 (PS-1), presenilin-2 (PS-2), or the amyloid precursor protein (APP) genes. METHODS: We used immunohistochemistry and confocal laser scanning microscopy to probe the brains of 22 patients with FAD (13 with PS-1, 5 with PS-2, and 4 with APP mutations) and 14 patients with SAD. RESULTS: AMY plaques were present in all SAD and FAD brains, including an FAD/PS-1 brain from an individual with preclinical disease. The morphology of AMY plaques in SAD and FAD brains was indistinguishable, but they differed from Abeta deposits because AMY plaques lacked an immunoreactive core. AMY plaques sometimes colocalized with Abeta(x-42) deposits, but they did not colocalize with Abeta(x-40) plaque cores in either SAD or FAD brains. The percent of cortical area occupied by AMY was greater in FAD than in SAD brains (mean percent area = 9.8% and 5.9%, t = 2.487, p = 0.018). In particular, APP and PS-1 cases had more AMY deposition than PS-2 or SAD cases (12.9%, 10.5%, 6.2% in APP, PS-1, and PS-2 AD). CONCLUSIONS: AMY plaques are consistently present in familial AD due to presenilin-1 (PS-1), PS-2, and amyloid precursor protein mutations, and they can begin to accumulate before the emergence of dementia.     

Mouse models of Alzheimer's disease: the long and filamentous road

Alzheimer's disease (AD) is characterized by memory impairment leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid beta peptide, A beta, whereas NFTs contain hyperphosphorylated forms of the microtubule-associated protein tau (tau). Familial AD (FAD) mutations either elevate A beta synthesis by favoring 'secretase' of the Alzheimer beta-amyloid precursor protein (APP) or enhance the fibrillogenic properties of this peptide. Mutations in the tau gene cause a different disease denoted FTPD-17, but suggest that the aberrant forms of tau seen in AD are unlikely to be benign. These findings imply a complex pathogenic cascade in AD and important goals of transgenic modeling are to capture and stratify this pathogenic process. Several laboratories have created APP transgenic (Tg) mice that exhibit AD-like amyloid pathology and A beta burdens. These Tg lines also exhibit deficits in spatial reference and/or working memory, with immunization against A beta attenuating both AD-associated phenotypes. Tangle-like pathologies are observed in mice expressing FTPD-17 mutant forms of tau, but florid tau pathologies based upon the wild type (wt) tau isoforms present in AD have proven more elusive. Creation of animal models with robust amyloid and tau pathologies, yet free of irrelevant confounding pathologies, remains a major objective in this field.     

Presenilins, β-amyloid precursor protein and the molecular basis of Alzheimer's disease

Progressive cerebral deposition of the 40- and 42-residue amyloid β-proteins is an early and invariant event in all forms of Alzheimer's disease (AD). Aβ proteins are generated from the β-amyloid precursor protein (APP) via two sequential cleavages by proteases designated β-secretase and γ-secretase and are constitutively secreted by essentially all cells throughout life. APP can undergo these cleavages during its secretory trafficking to the cell surface, yet much of Aβ appears to be generated after APP reaches the surface, i.e. in the endosomal pathway. Presenilin (PS) 1 and 2, homologous proteins with eight transmembrane (TM) domains, play a critical role in the γ-secretase cleavage of APP. Deletion of presenilin 1 (PS1) in mice markedly decreases Aβ production, whereas AD-causing PS1 mutations selectively increase Aβ₄₂ production, thereby markedly accelerating amyloid plaque formation, both in humans and transgenic mice. Small amounts of APP and PS can be co-immunoprecipitated from cells, suggesting a direct role of PS1 in the cleavage of APP by γ-secretase. We recently observed and mutated two unusual intramembranous aspartate residues in TM6 and TM7 of each presenilin, resulting in complete blockage of the γ-secretase cleavage of APP, with no detectable Aβ production by cells. Because our protease inhibitor studies suggest that γ-secretase is an aspartyl protease, we hypothesize that these two key aspartates serve as the active site of an unprecedented intramembranous aspartyl protease (i.e. γ-secretase). The recent discovery that Notch, a protein critical for cell fate determination during development, also undergoes an intramembranous cleavage mediated by PS suggests that presenilin may be a key regulatory enzyme for several vital proteolytic events. Thought of in this context, AD may arise late in the post-reproductive life of humans as an ancillary metabolic consequence of a proteolytic mechanism which confers strong evolutionary advantage. Specific and potent inhibitors of γ-secretase/presenilin or of the recently cloned β-secretase may well prove useful for the treatment and the prevention of AD.     

A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis

The amyloid hypothesis has dominated the thinking in our attempts to understand, diagnose and develop drugs for Alzheimer's disease (AD). This article presents a new hypothesis that takes into account the numerous familial AD (FAD) mutations in the amyloid precursor protein (APP) and its processing pathways, but suggests a new perspective beyond toxicity of forms of the amyloid beta-peptide (Abeta). Clearly, amyloid deposits are an invariable feature of AD. Moreover, although APP is normally processed to secreted and membrane-bound fragments, sAPPbeta and CTFbeta, by BACE, and the latter is subsequently processed by gamma-secretase to Abeta and CTFgamma, this pathway mostly yields Abeta of 40 residues, and increases in the levels of the amyloidogenic 42-residue Abeta (Abeta42) are seen in the majority of the mutations linked to the disease. The resulting theory is that the disease is caused by amyloid toxicity, which impairs memory and triggers deposition of the microtubule associated protein, Tau, as neurofibrillary tangles. Nevertheless, a few exceptional FAD mutations and the presence of large amounts of amyloid deposits in a group of cognitively normal elderly patients suggest that the disease process is more complex. Indeed, it has been hard to demonstrate the toxicity of Abeta42 and the actual target has been shifted to small oligomers of the peptide, named Abeta derived diffusible ligands (ADDLs). Our hypothesis is that the disease is more complex and caused by a failure of APP metabolism or clearance, which simultaneously affects several other membrane proteins. Thus, a traffic jam is created by failure of important pathways such as gamma-secretase processing of residual intramembrane domains released from the metabolism of multiple membrane proteins, which ultimately leads to a multiple system failure. In this theory, toxicity of Abeta42 will only contribute partially, if at all, to neurodegeneration in AD. More significantly, this theory would predict that focussing on specific reagents such as gamma-secretase inhibitors that hamper metabolism of APP, may initially show some beneficial effects on cognitive performance by elimination of acutely toxic ADDLs, but over the longer term may exacerbate the disease process by reducing membrane protein turnover.