Proteolytic processing of the Alzheimer's disease amyloid precursor protein in brain and platelets

Proteolytic processing of the amyloid precursor protein by beta -and gamma-secretases results in the production of Alzheimer's disease (AD) Abeta amyloid peptides. Modulation of secretase activity is being investigated as a potential therapeutic approach. Recent studies with human brain have revealed that the beta-secretase protein, BACE, is increased in cortex of AD patients. Analysis of betaCTF (or C99), the amyloid precursor protein (APP) product of BACE cleavage that is the direct precursor to Abeta, shows it is also elevated in AD, underlying the importance of beta-secretase cleavage in AD pathogenesis. The C-terminal product of gamma-secretase cleavage of APP, epsilonCTF (or AICD), is enriched in human brain cortical nuclear fractions, a subcellular distribution appropriate for a putative involvement of APP cytosolic domain in signal transduction. Analysis of AD cortex samples, particularly that of a carrier of a familial APP mutation, suggests that processing of APP transmembrane domain generates an alternative CTF product. All these particularities observed in the AD brain demonstrate that APP processing is altered in AD. The transgenic mouse model Tg2576 seems to be a promising laboratory tool to test potential modulators of Abeta formation. Indeed, C-terminal products of alpha-, beta-, and gamma-secretase cleavage are readily detectable in the brain of these transgenic mice. Finally, the finding of the same secretase products in platelets and neurons make platelets a potentially useful and easily accessible clinical tool to monitor effects of novel therapies based on inhibition of beta- or gamma-secretase.     

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 metabolism and secretases in Alzheimer’s disease

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid fibrils composed of the amyloid beta-protein (A beta) in senile plaques. A beta is derived from the beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavages. beta-secretase was recently identified to be a membrane-anchored aspartyl protease that is widely distributed in subcellular compartments, including Golgi, trans-Golgi network, and endosomes. Although definitive identification of gamma-secretase will require reconstituting its activity in vitro, mounting evidence suggests that gamma-secretase is an unusual intramembrane-cleaving aspartyl protease. Two intramembranous aspartate residues in presenilin (PS) are absolutely required for A beta generation. Three classes of gamma-secretase inhibitors can directly bind to PS, strongly supporting the hypothesis of PSI as gamma-secretase. These results provide the molecular basis for therapeutic interventions that reduce A beta accumulation in AD patients by inhibiting beta- or gamma-secretase.     

Gamma-secretase modulation with Abeta42-lowering nonsteroidal anti-inflammatory drugs and derived compounds

The amyloid-beta (Abeta) peptides and specifically the highly amyloidogenic isoform Abeta42 appear to be key agents in the pathogenesis of familial and sporadic forms of Alzheimer's disease (AD). The final step in the generation of Abeta from the amyloid precursor protein is catalyzed by the multiprotein complex gamma-secretase, which constitutes a prime drug target for prevention and therapy of the disease. However, highly potent gamma-secretase inhibitors that block formation of all Abeta peptides have provoked troubling side effects in preclinical animal models of AD. This toxicity can be readily explained by the promiscuous substrate specificity of gamma-secretase and its essential role in the NOTCH signaling pathway. For that reason and because of the crucial role of Abeta42 in the pathogenesis of the disease, selective inhibition of Abeta42 production would seem to be a more promising alternative to complete inhibition of gamma-secretase activity. This theoretical concept has edged much closer to clinical reality with the surprising finding that certain nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, and derived compounds display preferential Abeta42-lowering activity. In contrast to gamma-secretase inhibitors, these gamma-secretase modulators effectively suppress Abeta42 production while sparing processing of NOTCH and other gamma-secretase substrates. Although not fully resolved on the molecular level, the mechanism of action of Abeta42-lowering NSAIDs is independent of cyclooxygenase inhibition and most likely involves direct interaction with components of the gamma-secretase complex or its substrates. Current efforts to improve the pharmacological shortcomings of available gamma-secretase modulators will hopefully lead to the development of clinically useful Abeta42-lowering compounds in the near future.     

Commentary: Abeta N- Terminal Isoforms: Critical contributors in the course of AD pathophysiology

The assessment of protein or amino acid variations across evolution allows one to glean divergent features of disease-specific pathology. Within the Alzheimer's disease (AD) literature, extensive differences in Abeta processing across cell lines and evolution have clearly been observed. In the recent past, increased levels of amyloid beta Abeta1-42 have been heralded to be what distinguishes whether one is prone to the development of AD [59]. However, observations in naturally occurring, non-transgenic animals which display a great deal of parenchymal Abeta1-42 (Abeta found within extracellular plaque deposits) and a complete lack ofbeta1-40 within these same Abeta1-42 plaques raise the issue of whether Abetax-42 (Abeta that is truncated or modified at the N- terminus), rather than Abeta1-42, is instead the critical mediator of Abeta production and pathogenesis [47,49]. Distinct ratios of Abeta N-terminal variants (i.e. Abeta1-x, Abeta3-x, Abeta11-x, beta17-x) have been assessed in human amyloid plaques [18,21,40,41,42,47,48,49,52]. Moreover, ratios of specific Abeta N-terminal variants separate naturally occurring, non-transgenic animals which develop abundant levels of Abetax-42 and not Abetax-40 from human AD participants who harbor plaques that contain both the Abetax-42 and Abetax-40 variants [49]. Next, Teller and colleagues have demonstrated the presence of N-terminal truncated soluble 3kD (likely Abeta17-x) and 3.7kD peptides (in addition to 4kD Abeta) well before the appearance of amyloid plaques in Down Syndrome brain [51], indicating an early contribution of thebeta N-terminus to the formation of amyloid pathology. Additional critical facts concerning the major contribution of the Abeta N-terminus in AD pathogenesis include observations which support thatbeta generated by rodent neurons is predominantly truncated at Abeta11-x [13], the major form of APP C-terminal fragments in mice lacking functional PS1 is AbetaPP11-98 [9], beta11-x expression is increased as a function of BACE expression [55], and an interrelationship between presenilin-1 mutations and increased levels of N-terminally truncatedbeta [40]. This commentary highlights current understanding and potential biochemical, pathological, and cell biological contributions of Abeta N-terminal variants implicated during the course of AD pathogenesis. Although the amyloid beta protein precursor (AbetaPP) gene and Abeta are highly conserved across mammalian species, there are species-specific differences. For instance, the primate, guinea pig, canine, and polar bear share an identical Abeta sequence to that observed in human brain while the rat displays a distinct amino acid sequence with substitutions at residues 5 (Arg), 10 (Tyr), and 13 (His) [24,37]. All of these mammals generate Abeta1-42 via cleavage by at least two enzymes, beta (beta-) secretase and gamma (gamma-) secretase (Fig. 1). The enzyme that liberates the N- terminus of the Abeta peptide ('beta-secretase') is also termed BACE (beta-site AbetaPP cleaving enzyme) [55]. Cathepsin D, which accumulates within AD neurons [15], also cleaves at the N-terminal side of the first aspartate residue of amyloid beta [2].beta-secretase activity is necessary in order to initiate 4kD beta1-x formation by cleaving AbetaPP at the N-terminus and results in the release of a soluble 100kD AbetaPP N- terminal fragment and a 12kD membrane bound C-terminal fragment (C99/C100) [55]. The carboxyl-terminus of the Abetapeptide is liberated through cleavage by the enzyme termed gamma-secretase. In the past, potential AD therapeutic strategies have mainly been geared towards gamma-secretase inhibition. However, such strategies alone no longer appear sound as it is clear that the AbetaPP C99/C100 fragment itself, which requires beta-, but not gamma-, secretase cleavage for generation and includes the entire Abeta peptide, is neurotoxic when evaluated in cultured cells [12,30,34]. Thus, gamma-secretase inhibition alone would not preclude the generation of the neurotoxic C99/C100 fragment.     

BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

Evidence suggests that beta-amyloid (Abeta) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer's disease (AD). However, the causal link between Abeta and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the beta-secretase (BACE1) not only abrogates Abeta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that Abeta ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD.     

BACE1 structure and function in health and Alzheimer's disease

Amyloid plaques, hallmark neuropathological lesions in Alzheimer's disease (AD) brain, are composed of the beta-amyloid peptide (Abeta). Much evidence suggests that Abeta is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. Given the strong correlation between Abeta and AD, therapeutic strategies to lower cerebral Abeta levels should prove beneficial for AD treatment. Abeta is derived from amyloid precursor protein (APP) via cleavage by two proteases, beta- and gamma-secretase. The beta-secretase has been identified as a novel aspartic protease named BACE1 (beta-site APP Cleaving Enzyme 1) that initiates Abeta formation. Importantly, BACE1 appears to be dysregulated in AD. As the rate-limiting enzyme in Abeta generation, BACE1, in principle, is an excellent therapeutic target for strategies to reduce the production of Abeta in AD. While BACE1 knockout (BACE1-/-) mice have been instrumental in validating BACE1 as the authentic beta-secretase in vivo, data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-/- mice. Here we review the basic biology of BACE1, focusing on the regulation, structure and function of this enzyme. We pay special attention to the putative function of BACE1 during normal conditions and discuss in detail the relationship that exists between key risk factors for AD and the pathogenic alterations in BACE1 that are observed in the diseased state.     

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.     

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.     

Filling the gaps in the abeta cascade hypothesis of Alzheimer's disease

Advances in the understanding of Alzheimer's disease (AD) pathogenesis provide strong support for a modified version of the amyloid cascade hypothesis, which is now often referred to as the amyloid beta protein (Abeta) cascade hypothesis. The basic tenant of this modified hypothesis is that Abeta aggregates trigger a complex pathological cascade leading to neurodegeneration. Thus, as opposed to the original amyloid hypothesis, whose basic tenant was that amyloid deposits cause AD, the Abeta hypothesis is more inclusive in that it takes into account the possibility that several different Abeta assemblies might contribute to AD pathogenesis and not merely the detectable amyloid deposits within the brain. Significantly, the Abeta hypothesis has provided the rationale for a plethora of therapeutic interventions that target Abeta production, aggregation or clearance. Indeed, AD research is entering an exciting phase in which strategies derived from basic research will be tested in humans. Despite this progress, many aspects of AD pathogenesis, particularly those downstream of Abeta accumulation are not well understood. Herein, we explore several observations that serve to illustrate the more enigmatic aspects of the Abeta hypothesis, and discuss why further basic research may be critical in order to develop therapies designed to halt neurodegeneration and reverse cognitive decline in patients already suffering from AD 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.     

Alzheimer's disease

Alzheimer's disease (AD) is the most commonly diagnosed etiology of dementia and may be caused by the progressive accumulation and deposition of neurotoxic Abeta/amyloid plaques and aggregates in brain with aging-the amyloid hypothesis of AD. However, Abeta/amyloid deposition is likely necessary but not sufficient to cause AD, and other putative downstream pathologies, including the aggregation of phospho-tau in neurofibrillary tangles, synaptic and neuronal loss, and glial and inflammatory responses, are likely equally important to AD pathogenesis. The majority of AD is sporadic (> 95%) but the discovery of rare early onset familial forms of AD has been pivotal to our understanding of its pathogenesis and in developing novel therapeutic strategies. Currently available drugs for patients with AD provide modest, temporary, and palliative benefits, but they consistently demonstrate safety and efficacy on cognitive, functional, behavioral, and global outcome measures. Novel potential disease-modifying therapies now in preclinical research or clinical trials may be more effective in preventing or arresting the progressive dementia of AD and will provide a test of the amyloid hypothesis.     

JLK inhibitors: isocoumarin compounds as putative probes to selectively target the gamma-secretase pathway

Alzheimer's disease is characterized by the extracellular deposition of the amyloid beta-peptide that derives from its precursor betaAPP by sequential actions of beta- and gamma- secretases, respectively. Recent studies aimed at identifying these enzymes have been reported as it is thougth that their inhibition should hopefully lead to reduce Abeta load in the AD brains. beta-secretase seems to be due to BACE1, a novel membrane-bound aspartyl protease. gamma-secretase identification is still a matter of controversy. Invalidation of presenilin genes was reported to impair both gamma-secretase-mediated Abeta production and Notch cleavage leading to NICD production. This observation together with another biochemical and pharmacological evidences led to suggest that presenilins could be the genuine long-searched gamma-secretase that would be responsible for both APP and Notch cleavages. We have designed novel non peptidic potential inhibitors of gamma-secretase (referred to as JLK inhibitors) and examined their ability to prevent Abeta40 and Abeta42 secretions as well as NICD production. Three out of a series of these agents drastically lower the recoveries of both Abeta40 and Abeta42 produced by betaAPP-expressing cell lines and concomitantly protect intracellular C99 and C83 recoveries. These inhibitors also prevent Abeta40/42 productions by C99-expressing cells. Interestingly, these inhibitors were totally unable to affect the DeltaENotch cleavage leading to NICD generation. Here, we also further characterize the pharmacological properties and specificity of these JLK inhibitors.     

The Amyloid Hypothesis and the clearance and degradation of Alzheimer's beta-peptide

The second generation of therapeutic strategies for Alzheimer's disease (AD) embraces the Amyloid Hypothesis, which asserts that through a series of events not completely understood, misfolding of the amyloid-beta (Abeta) peptide is a primary event eliciting neurodegeneration and AD pathology. A variety of approaches are being tried to interrupt the disease process, including reducing the production of the Abeta peptide, inhibiting its aggregation, and promoting its removal, for example via immunotherapy. The success of anti-Abeta disease-modifying approaches in eliminating the postulated etiologic form(s) of the peptide will ultimately depend on biological clearance and degradation of the various forms of the Abeta peptide from the brain compartment. Little is known about exchange of the Abeta peptide between the brain and blood. Increased understanding of this process in experimental animal models and humans, and how it changes with aging, will likely open new therapeutic avenues. It will also be needed to properly design early clinical trials to verify the efficacy of potential drug candidates working through the Abeta peptide.     

gamma-Secretase modulators

gamma-Secretase is responsible for the final cut of the amyloid beta-peptide (Abeta) precursor (APP) to produce the Abeta peptide implicated the pathogenesis of Alzheimer's disease (AD). Thus, this protease is a top target for the development of AD therapeutics. gamma-Secretase is a complex of four different integral membrane proteins, with the multi-pass presenilin being the catalytic component of a novel intramembrane-cleaving aspartyl protease. gamma-Secretase cleaves other substrates besides APP, the most notorious being the Notch receptor that is required for many cell differentiation events. Because proteolysis of Notch by gamma-secretase is essential for Notch signaling, interference with this process by gamma-secretase inhibitors can cause severe toxicities. Thus, the potential of gamma-secretase as therapeutic target likely depends on the ability to selectively inhibit Abeta production without hindering Notch proteolysis. The discovery of compounds capable of such allosteric modulation of the protease activity has revived gamma-secretase as an attractive target. Structural modification of these gamma-secretase modulators through medicinal chemistry should lead to in vivo active agents suitable for clinical trials.     

Gamma-secretase inhibition and modulation for Alzheimer's disease

Gamma-secretase is a multi-protein complex that proteolyzes the transmembrane region of the amyloid beta-peptide (Abeta) precursor (APP), producing the Abeta peptide implicated in the pathogenesis of Alzheimer's disease (AD). This protease has been a top target for AD, and various inhibitors have been identified, including transition-state analogue inhibitors that interact with the active site, helical peptides that interact with the initial substrate docking site, and other less peptide-like, more drug-like compounds. Although one gamma-secretase inhibitor has advanced into late-phase clinical trials, concerns about inhibiting this protease remain. The protease complex cleaves a number of other substrates, and in vivo toxicities observed with gamma-secretase inhibitors are apparently due to blocking one particularly important substrate, the Notch receptor. Thus, the potential of gamma-secretase as therapeutic target likely depends on the ability to selectively inhibit Abeta production without hindering Notch proteolysis (i.e., modulation rather than inhibition). The discovery of gamma-secretase modulators has revived gamma-secretase as an attractive target and has so far resulted in one compound in late-phase clinical trials. The identification of other modulators in a variety of structural classes raise the hope that more promising agents will soon be in the pipeline.     

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.     

Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease

Cerebrovascular dysfunction contributes to the cognitive decline and dementia in Alzheimer's disease (AD), and may precede cerebral amyloid angiopathy and brain accumulation of the Alzheimer's neurotoxin, amyloid beta-peptide (Abeta). The blood-brain barrier (BBB) is critical for brain Abeta homeostasis and regulates Abeta transport via two main receptors, the low density lipoprotein receptor related protein 1 (LRP1) and the receptor for advanced glycation end products (RAGE). According to the neurovascular hypothesis of AD, faulty BBB clearance of Abeta through deregulated LRP1/RAGE-mediated transport, aberrant angiogenesis and arterial dysfunction may initiate neurovascular uncoupling, Abeta accumulation, cerebrovascular regression, brain hypoperfusion and neurovascular inflammation. Ultimately these events lead to BBB compromise and chemical imbalance in the neuronal 'milieu', and result in synaptic and neuronal dysfunction. Based on the neurovascular hypothesis, we suggest an array of new potential therapeutic approaches that could be developed for AD to reduce neuroinflammation, enhance Abeta clearance and neurovascular repair, and improve cerebral blood flow. RAGE-based and LRP1-based therapeutic strategies have potential to control brain Abeta in AD, and possibly related familial cerebrovascular beta-amyloidoses. In addition, we have identified two vascularly restricted genes, GAX (growth arrest-specific homeobox), which controls LRP1 expression in brain capillaries and brain angiogenesis, and MYOCD (myocardin), which controls contractility of cerebral arterial smooth muscle cells and influences cerebral blood flow. These findings provide insights into new pathogenic pathways for the vascular dysfunction in AD and point to new therapeutic targets for AD.     

New developments in mild cognitive impairment and Alzheimer's disease

PURPOSE OF REVIEW: In this paper, we review current concepts of Alzheimer's disease, recent progress in diagnosis and treatment and important developments in our understanding of its pathogenesis with a focus on beta-amyloid both as culprit and therapeutic target. RECENT FINDINGS: The amyloid cascade hypothesis of Alzheimer's disease pathogenesis continues to predominate with evidence suggesting that small oligomeric forms of Abeta-42 rather than fibrils or senile plaques are the key pathological substrates. The concept of mild cognitive impairment continues to be refined to define better those patients who will progress to Alzheimer's disease. Structural and functional imaging techniques and cerebrospinal fluid biomarkers are gaining acceptance as diagnostic markers of Alzheimer's disease, with a potentially exciting advance being the ability to image amyloid in vivo using novel positron emission tomography ligands. Whilst available treatments afford only symptomatic benefits, disease-modifying treatments may be within reach. Despite the halting of the first amyloid beta-vaccination trial due to adverse effects, amyloid immunotherapy continues to show promise, with new approaches already entering clinical trials. Other therapeutic strategies under investigation include inhibition of beta -and gamma-secretase, key enzymes implicated in Alzheimer's disease pathogenesis. SUMMARY: Current research demonstrates the potential for diagnostic strategies and disease modifying treatments to follow from an ever more detailed understanding of the molecular mechanisms underlying the pathogenesis of Alzheimer's disease.     

Treatment of Alzheimer's disease: current and future therapeutic approaches

The pathophysiology of Alzheimer's disease (AD) includes the deposition of amyloid beta protein (Abeta) and the ensuing initiation of a variety of secondary processes, including tau hyperphosphorylation, excitotoxicity, oxidation, and inflammation. Nerve cell loss in structures responsible for manufacturing neurotransmitters results in a variety of neurochemical deficits. Current therapeutic approaches to the treatment of AD include cholinesterase inhibitors for mild to moderate disease, memantine for moderate to severe disease, and vitamin E or selegiline. Reduction of Abeta generation or aggregation, enhancement of Abeta removal, interruption of tau hyperphosphorylation, and the use of more efficacious antioxidant or anti-inflammatory agents represent promising therapeutic strategies currently being investigated. Improved methodologies for clinical trial design and analysis and the development of biological markers may hasten the identification of effective treatments for AD.