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.     

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.     

beta-amyloid cascade: current status and future directions]

The deposition of amyloid beta peptides (A beta) is one of the pathological hallmarks of Alzheimer's disease (AD) brains. A beta are composed of 40-42 amino acid peptides that are proteolytically cleaved from beta APP. The deposition as diffuse plaques of a species of A beta ending at the 42nd residue (A beta 42) is one of the earliest pathological changes of AD. Importantly, mutations in beta APP genes located in positions flanking the A beta sequences have been shown to cosegregate with the clinical manifestations of AD in a subset of familial AD (FAD) pedigrees. Moreover, mutations in presenilin (PS) 1 and 2, novel polytopic membrane proteins identified as causative molecules for the majority of FAD, also increase the production of A beta 42. These results support the notion that A beta (42) plays a key role in the cascadic development of AD. Recently, PS 1 and PS 2 are shown to be the catalytic subunits of gamma-secretase that cleave the intramembrane segments of beta APP and Notch. Future therapeutic approaches to reduce amyloid deposition, including inhibitors for beta- and gamma-secretases, as well as beta-amyloid vaccine therapy, raise high hopes towards the cure and prevention of AD, although the outcome thereof would be key to the consistency of amyloid cascade hypothesis.     

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.     

BACE1: the beta-secretase enzyme in Alzheimer's disease

Data that have accumulated for well over a decade have implicated the beta-amyloid (Abeta) peptide as a central player in the pathogenesis of Alzheimer's disease (AD). Amyloid plaques, composed primarily of Abeta progressively form in the brains of AD patients, and mutations in three genes (amyloid precursor protein [APP] and presenilin 1 and 2 [PS1 and PS2]) cause early-onset familial AD (FAD) by directly increasing production of the toxic, plaque-promoting Abeta42 peptide. Given the strong association between Abeta and AD, it is likely that therapeutic strategies to lower the levels of Abeta in the brain should prove beneficial for the treatment of AD. One such strategy could involve inhibiting the enzymes that generate Abeta. Abeta is a product of catabolism of the large type-I membrane protein APP. Two proteases, called beta- and gamma-secretase, endoproteolyze APP to liberate the Abeta peptide. Recently, the molecules responsible for these proteolytic activities have been identified. Several lines of evidence suggest that the PS1 and PS2 proteins are gamma-secretase, and the identity of beta-secretase has been shown to be the novel transmembrane aspartic protease, beta-site APP-cleaving enzyme 1 (BACE1; also called Asp2 and memapsin 2). BACE2, a protease homologous to BACE1, was also identified, and together the two enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the functional properties of beta-secretase, and as the key enzyme that initiates the formation of Abeta, BACE1 is an attractive drug target for AD. This review discusses the identification and initial characterization of BACE1 and BACE2, and summarizes recent studies of BACE1 knockout mice that have validated BACE1 as the authentic beta-secretase in vivo.     

Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexes

gamma-Secretase is a protease complex, which catalyzes the final of two subsequent cleavages of the beta-amyloid precursor protein (APP) to release the amyloid-beta peptide (Abeta) implicated in Alzheimer's disease (AD) pathogenesis. In human cells, six gamma-secretase complexes exist, which are composed of either presenilin (PS) 1 or 2, the catalytic subunit, nicastrin, PEN-2, and either APH-1a (as S or L splice variants) or its homolog APH-1b. It is not known whether and how different APH-1 species contribute to the pathogenic activity of gamma-secretase complexes with familial AD (FAD)-associated mutant PS. Here we show that all known gamma-secretase complexes are active in APP processing and that all combinations of APH-1 variants with either FAD mutant PS1 or PS2 support pathogenic Abeta(42) production. Since our data suggest that pathogenic gamma-secretase activity cannot be attributed to a discrete gamma-secretase complex, we propose that all gamma-secretase complexes have to be explored and evaluated for their potential as AD drug target.     

beta-Secretase cleavage of the amyloid precursor protein mediates neuronal apoptosis caused by familial Alzheimer's disease mutations.

The amyloid precursor protein (APP) is cleaved by two enzymes, beta-secretase and gamma-secretase, to generate the pathological amyloid beta (Abeta) peptide. Expression of familial Alzheimer's disease (FAD) mutants of APP in primary neurons causes both intracellular accumulation of the C-terminal beta-secretase cleavage product of APP and increased secretion of Abeta, and eventually results in apoptotic death of the cells. To determine whether either of these two processing products of APP is involved in this apoptotic pathway, we first modeled experimentally the accumulation of the beta-secretase cleavage product in neurons. The C-terminal 100 amino acids (C100) of APP, with and without a signal peptide, was expressed in cells via recombinant herpes simplex virus (HSV) vectors. Both transgene products were targeted to the membrane, and both caused apoptosis in the neurons, implicating the beta-secretase cleavage product of APP in apoptosis caused by FAD APPs. Expression in neurons of a mutant of FAD APP that inhibited beta-secretase cleavage inhibited its ability to cause apoptosis. However, expression in neurons of a mutant of FAD APP that inhibited gamma-secretase cleavage did not inhibit the ability of this mutant to cause apoptosis. These data suggested that the C-terminal beta-secretase cleavage product of APP, but not Abeta, mediates the apoptosis caused by FAD mutants of APP. Consistent with this hypothesis, C31, which is generated from the beta-secretase cleavage product, itself caused neuronal apoptosis. Inhibitors of caspases 3, 6 and 8, but not of caspase 9, inhibited the apoptosis caused by FAD mutants of APP. It may be inferred from these data that beta-secretase cleavage of FAD mutants of APP allows the appropriate caspase access to its site of action to produce C31, which directly causes neuronal apoptosis.     

A comparative assessment of gamma-secretase activity in transgenic and non-transgenic rodent brain

Amyloid-beta (Abeta) deposits are one of the hallmarks of the neuropathological degeneration observed in Alzheimer's disease (AD) and Abeta concentrations have been reported to vary in different brain regions of AD patients. Abeta is produced by the sequential cleavage of amyloid precursor protein (APP) by beta-secretase and gamma-secretase, respectively. Previous studies have shown that over-expression of the gamma-secretase complex leads to increased gamma-secretase proteolytic activity increasing Abeta production. However, it is not known whether brain regions with highest Abeta concentration also express relatively higher levels of gamma-secretase activity. Accordingly, the relationship between Abeta levels and gamma-secretase activity across brain regions was investigated and correlated in the brains of transgenic and non-transgenic rodents commonly used in AD research. The data demonstrated that Abeta levels do vary in different brain regions in both transgenic and non-transgenic mice but are not correlated with regional gamma-secretase activity. Furthermore, this study demonstrated that while mutations in the APP and PS1 sequences affect the absolute Abeta levels this is not reflected in an increase in gamma-secretase proteolytic activity. The data in the current paper indicate that this assay is able to measure the level of gamma-secretase activity in rodent species. Using this methodology will aid our understanding of physiological gamma-secretase function.     

Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease

Rigorous scientific research has identified multiple interactive mechanisms that parallel and are likely causative of the development of Alzheimer's disease (AD). Causative mechanisms include genomics, the creation of amyloid beta (Abeta), factors inhibiting the Abeta removal process, the transformation of Abeta to its toxic forms (various forms of Abeta aggregation), and lastly the oxidative, inflammatory, and other effects of toxic Abeta. Fibrillar beta-amyloid peptide, a major component of senile plaques in AD brain, is known to induce microglial-mediated neurotoxicity under certain conditions, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. Abeta-42 oligomers that are soluble and highly neurotoxic, referred to as Abeta-derived diffusible ligands (ADDLs), assemble under conditions that block fibril formation. These oligomers bind to dendrite surfaces in small clusters with ligand-like specificity and are capable of destroying hippocampal neurons at nanomolar concentrations. Evidence is presented that AD is triggered by these soluble, neurotoxic assemblies of Abeta rather than the late stage pathology landmarks of amyloid plaques and tangles. The premise is that AD symptoms stem from aberrant nerve cell signaling and synaptic failure rather than nerve cell death, which nevertheless follows and exacerbates the initial pathologies of AD. The defective clearance of amyloid leads to amyloid angiopathy that in turn perpetuates hypoperfusion that affects formation as well as absorption of CSF thereby altering clearance of amyloid and promoting vascular and parenchymal deposition[1]. Hypoperfusion, the defective clearance of amyloid, and resultant increase in amyloid deposition thus represent a vicious cycle. Chronic vascular hypoperfusion-induced mitochondrial failure results in oxidative damage, which drives caspase 3-mediated Abeta peptide secretion and enhances amyloidogenic APP processing. Intracellular Abeta accumulation in turn promotes a significant oxidative and inflammatory mechanism that generates a vicious cycle of Abeta generation and oxidation, each accelerating the other. Abeta activates astrocytes that add to the oxidative imbalance, upregulate the expression of APP via TGF-beta, and are capable of expressing BACE1. Each of these 3 actions accelerates the larger cycle of cholinergic neuron destruction. As oxidative stress induces lesions of cholinergic nuclei producing a reduction in cholinergic neurotransmission, a subsequent increase in cortical APP involving PKCepsilon leads to accelerated amyloidogenic APP metabolism. The linkage of cholinergic activation and APP metabolism completes an additional feedback loop wherein the damage wrought by Abeta accelerates further Abeta production. A comprehensive vision of the neuropathophysiologic mechanisms that result in AD reveals several vicious cycles within a larger vicious cycle, that is to say, a number of interactive systems that each, once set in motion, amplify their own processes, thus accelerating the development of AD.     

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.     

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.     

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.     

Amyloid precursor protein compartmentalization restricts β-amyloid production

Alzheimer's disease (AD) is defined by deposits of the 42-residue amyloid-beta peptide (Abeta42) in the brain. Abeta42 is a minor metabolite of the amyloid precursor protein (APP), but its relative levels are increased by mutations on APP and presenilins 1 and 2 linked to familial AD. beta-secretase (BACE-1), an aspartyl protease, cleaves approx 10% of the APP in neuronal cells on the N-terminal side of Abeta to produce the C-terminal fragment (CTFbeta), which is cleaved by gamma-secretase to produce mostly Abeta of 40 residues (90%) and approx10% Abeta42. A third enzyme, alpha-secretase, cleaves APP after Abeta16 to secrete sAPPalpha and CTFalpha, the major metabolites of APP. Moreover, previous studies have demonstrated that phorbol esters stimulate processing of APP by alpha-secretase. Because alpha-secretase and BACE-1 cleave APP within the secretory pathway, it is likely that the two enzymes compete for the APP substrate. This type of competition can explain the failure to saturate the minor BACE-1 pathway by overexpressing APP in the cell. In this study, we demonstrate that inhibition of constitutive alpha-secretase processing in a human neuroblastoma cell line does not increase the yield of Abeta, suggesting that the APP substrate targeted for alpha-secretase processing is not diverted to the BACE-1 pathway. However, when phorbol ester-induced alpha-secretase was similarly inhibited, we detected an increase in BACE-1 processing and AB yield. We explain these results compartmentalization of BACE-1 and alpha-secretase with processing depending on sorting of APP to the two compartments. The simplest explanation for the detection of competition between the two pathways upon phorbol ester stimulation is the partial failure of this compartmentalization by phorbol ester-induced release of secretory vesicles.     

Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains

Buoyant membrane fractions containing presenilin 1 (PS1), an essential component of the gamma-secretase complex, and APP CTFbeta, a gamma-secretase substrate, can be isolated from cultured cells and brain by several different fractionation procedures that are compatible with in vitro gamma-secretase assays. Analysis of these gradients for amyloid beta protein (Abeta) and CTFgamma production indicated that gamma-secretase activity is predominantly localized in these buoyant membrane microdomains. Consistent with this localization, we find that gamma-secretase activity is cholesterol dependent. Depletion of membrane cholesterol completely inhibits gamma-secretase cleavage, which can be restored by cholesterol replacement. Thus, altering cholesterol levels may influence the development of Alzheimer's disease (AD) by influencing production and deposition of Abeta within cholesterol rich membrane microdomains.     

Mutations in APP have independent effects on Abeta and CTFgamma generation

Understanding the molecular mechanism of beta-amyloid (Abeta) generation is crucial for Alzheimer's disease pathogenesis as well as for normal APP function. The transmembrane domain (TM) of APP appears to undergo presenilin-dependent gamma-secretase cleavage at two topologically distinct sites: a site in the middle of the TM domain that is crucial for the generation of Abeta-peptides, and a site close to the cytoplasmic border (S3-like/epsilon site) of the TM domain that leads to production of the APP intracellular domain (CTFgamma/AICD). We demonstrate that, in contrast to the unique effect of familial Alzheimer's disease (FAD) mutations in APP on Abeta42 production, some but not all FAD mutations also affect CTFgamma generation. Furthermore, changes in total CTFgamma levels do not correlate with either an increase or a decrease of any Abeta species, and inhibition of Abeta-peptide formation starting from position +1 (Abeta1-x) does not affect CTFgamma production. These results suggest that cleavage at the gamma40/42- and the S3-like sites can be dissociated, and that APP signaling and Abeta production are not tightly linked.     

Genetic and pharmacological basis for therapeutic inhibition of beta- and gamma-secretases in mouse models of Alzheimer's memory deficits

Alzheimer's disease (AD) is a dementing neurodegenerative disorder for which effective disease-modifying therapeutic treatments have not yet been developed. Genetic and molecular biological studies provide accumulating evidence supporting the hypothesis that the production of amyloid-beta (Abeta) peptides, especially neurotoxic Abeta42, is central to the pathophysiology of AD--the 'amyloid cascade' hypothesis. Abeta is proteolytically generated from a type I integral membrane amyloid precursor protein by the sequential action of two enzymes, called beta- and gamma-secretase, in reference to their cleavage sites at the N- and C-terminals, respectively. Given the strong association between Abeta and AD, the strategies to inhibit the production of Abeta, the first step of the amyloid cascade, should prove beneficial as truly disease-modifying therapeutic approaches for the treatment of AD. Recent advances in genetic strategies including knockouts, transgenics and virus-delivered small interfering RNAs and the development of potent and specific small-molecule inhibitors have opened a new window to test the impacts of beta- and gamma-secretase inhibition in vivo. Since cognitive deficits are at the heart of AD, one of the most important challenges is to determine the therapeutic potential of secretase-inhibiting approaches for AD-related memory deficits, linking perspectives through the prism of molecular/pathological events and those through behavioral and neurophysiological manifestations. I review recent progress in this field, with special focus on the functional consequences of beta- and gamma-secretase inhibition and altered amyloid neuropathology in mouse models of AD memory deficits.     

Genetic programming by the proteolytic fragments of the amyloid precursor protein: somewhere between confusion and clarity

Mice engineered to overexpress disease-causing mutant amyloid precursor proteins (APP) display plaque deposition, but lack the hyperphosphorylated tau and massive neuronal loss characteristic of Alzheimer's disease (AD). Global gene expression profiles of brain regions from AD patients show upregulation of proapoptotic and inflammatory genes and down-regulation of neurotrophic, MAPK, phosphatase, and synaptic genes, while a profile of mice overexpressing a mutant APP shows the opposite trends in apoptotic and neurotrophic genes. The proteolytic fragments of the amyloid precursor protein have distinct biological actions. Both the gamma-secretase cleaved COOH-terminal fragment (CTFgamma) and the alpha-secretase cleaved NH2-terminal of APP (sAPPalpha) can regulate gene expression. While Abeta and CTFgamma can lead to toxicity and cell death, sAPPalpha promotes neurite outgrowth, enhances memory, and protects against a variety of insults, including Abeta toxicity. In AD, Abeta levels increase while sAPPalpha levels decrease. These subtleties in the levels of APP cleavage products are not reproduced in mice overexpressing mutant APP. In fact, the gene expression changes driven by sAPPalpha, such as increases in transthyretin and insulin-like growth factor 2, may protect these mice from high levels of Abeta.     

Alzheimer's disease: a dysfunction of the amyloid precursor protein(1)

In this review, we argue that at least one insult that causes Alzheimer's disease (AD) is disruption of the normal function of the amyloid precursor protein (APP). Familial Alzheimer's disease (FAD) mutations in APP cause a disease phenotype that is identical (with the exception that they cause an earlier onset of the disease) to that of 'sporadic' AD. This suggests that there are molecular pathways common to FAD and sporadic AD. In addition, all individuals with Down syndrome, who carry an extra copy of chromosome 21 and overexpress APP several-fold in the brain, develop the pathology of AD if they live past the age of 40. These data support the primacy of APP in the disease. Although APP is the source of the beta-amyloid (Abeta) that is deposited in amyloid plaques in AD brain, the primacy of APP in AD may not lie in the production of Abeta from this molecule. We suggest instead that APP normally functions in the brain as a cell surface signaling molecule, and that a disruption of this normal function of APP is at least one cause of the neurodegeneration and consequent dementia in AD. We hypothesize in addition that disruption of the normal signaling function of APP causes cell cycle abnormalities in the neuron, and that these abnormalities constitute one mechanism of neuronal death in AD. Data supporting these hypotheses have come from investigations of the molecular consequences of neuronal expression of FAD mutants of APP or overexpression of wild type APP, as well as from identification of binding proteins for the carboxyl-terminus (C-terminus) of APP.     

Intracellular pH regulates amyloid precursor protein intracellular domain accumulation

The amyloid precursor protein (APP) metabolism is central to pathogenesis of Alzheimer's disease (AD). Parenchymal amyloid deposits, a neuropathological hallmark of AD, are composed of amyloid-beta peptides (Abeta). Abeta derives from the amyloid precursor protein (APP) by sequential cleavages by beta- and gamma-secretases. Gamma-secretase cleavage releases the APP intracellular domain (AICD), suggested to mediate a nuclear signaling. Physiologically, AICD is seldom detected and thus supposed to be rapidly degraded. The mechanisms responsible of its degradation remain unknown. We used a pharmacological approach and showed that several alkalizing drugs induce the accumulation of AICD in neuroblastoma SY5Y cell lines stably expressing APP constructs. Moreover, alkalizing drugs induce AICD accumulation in naive SY5Y, HEK and COS cells. This accumulation is not mediated by the proteasome or metallopeptidases and is not the result of an increased gamma-secretase activity since the gamma-secretase cleavage of Notch1 and N-Cadherin is not affected by alkalizing drug treatments. Altogether, our data demonstrate for the first time that alkalizing drugs induce the accumulation of AICD, a mechanism likely mediated by the endosome/lysosome pathway.