Amyloid beta-peptide: the inside story

The amyloid beta-peptide (Abeta) plays an early and critical role in the pathogenic cascade leading to Alzheimer's disease (AD). Abeta is typically found in extracellular amyloid plaques that occur in specific brain regions in the AD and Down syndrome brain. Mounting evidence, however, indicates that intraneuronal accumulation of this peptide may also contribute to the cascade of neurodegenerative events that occur in AD and Down syndrome. A pathogenic role for intracellular Abeta is not without precedent, as it is known to be an early and integral component of the human muscle disorder inclusion body myositis (IBM). Therefore, it is plausible that intracellular Abeta may likewise induce cytopathic effects in the CNS, causing neuronal and synaptic dysfunction and perhaps even neuronal loss. Here we review recent evidence supporting a pathogenic role for intracellular Abeta in AD, Down syndrome, and IBM.     

Cerebrospinal fluid levels of beta-amyloid(42) in patients with Alzheimer's disease are related to the exon 2 polymorphism of the cathepsin D gene

The intracellular aspartyl protease cathepsin D (catD) is involved in such Alzheimer's disease (AD)-related processes as the activation of the endosomal/lysosomal system and the cleavage of the amyloid precursor protein into amyloidogenic components, which may initiate neurodegeneration. A non-synonymous polymorphism (exon 2, C to T exchange leading to ala-->val substitution) of the gene encoding catD (CTSD) was previously associated with AD, in that the T allele increased the risk for AD. To investigate whether the T allele is associated with disease-related traits, we measured the concentration of the amyloid beta-peptide 1-42 (Abeta(42)) and 1-40 (Abeta(40)) in patients and control subjects. The T allele of the CTSD genotype was associated with a 50% decrease in Abeta(42) levels in the cerebrospinal fluid. Thus, we demonstrate a significant impact of the CTSD genotype on Abeta(42) levels in the cerebrospinal fluid of AD patients and underpin the importance of the validation of susceptibility genes by examining their potential pathophysiological relevance.     

Potentially amyloidogenic fragment of 50 kDa and intracellular processing of amyloid precursor protein in cells cultured under leupeptin

The principal neuropathological feature of Alzheimer's disease is extracellular deposition of 4-kDa proteinous fragment, designated as β-amyloid peptides (β/A4 peptides) derived by proteolytic cleavage from amyloid precursor protein (APP), a large cell-surface receptor-like protein. There has been evidence that APP is proteolytically degraded in the secretory and endosomal/lysosomal pathways. The pathway in which APP is cleaved to generate β/A4 peptides is still not identified. To clarify the intracellular processing of APP into the generation of β/A4 peptides, we detected and characterized potentially amyloidogenic or non-amyloidogenic fragments using newly established monoclonal and polyclonal antibodies in the cultured cells with or without leupeptin, potent lysosomal protease inhibitor of lysosome. APP fragments of 50 and 20 kDa containing full-length β/A4 peptides were identified in the cultured cells. Immunoblot analysis, biochemical study for specific marker enzyme activity of the fractions obtained from subcellular fractionation, sucrose density gradient centrifugation indicated that the 50-kDa APP fragment was produced in the compartment closely related to endosomal/lysosomal system. Our data suggest that the endosomal/lysosomal pathway is involved in the processing and generation of β/A4 peptides.     

Differential expression of carboxyl terminal derivatives of amyloid precursor protein among cell lines.

Understanding the pathway for amyloid percursor protein (APP) catabolism has become an important line of investigation. APP is a ubiquitous membrane bound protein that is rapidly cleaved at the membrane, yielding a secreted protein identical to protease nexin II and an internalized 11.5 kDa 100 residue C terminal derivative (CTD). The levels of CTDs in a variety of cell lines have been examined and were found to differ. Cell types associated with the pathology of Alzheimer's disease (AD), such as olfactory neuroblasts (ON) and cortical vascular endothelial cells, have higher levels of CTDs than lymphoblasts and melanoma cells. The mechanism of CTD catabolism appears to involve the lysosome because blockade of lysosomal but not endosomal or mitochondrial function results in increased levels of CTDs. Under these conditions, production of larger, amyloidogenic CTDs is also seen. In cells possessing higher levels of CTDs we find that the mechanism for production of amyloidogenic CTDs may involve the internalization of intact full-length APP. Thus, inhibition of the lysosomal system appears capable of generating amyloidogenic peptides. The amount of amyloidogenic peptides appears to vary among cell lines. Such variation may shed light on why amyloid accumulates around specific cell types such as vascular endothelial cells, neurons, and glia. Finally, disfunction of the lysosomal system may play a role in the pathogenesis of Alzheimer's disease.     

Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease

Genetic evidence strongly supports the view that Abeta amyloid production is central to the cause of Alzheimer's disease. The kinetics, compartmentation, and form of Abeta and its temporal relation to the neurodegenerative process remain uncertain. The levels of soluble and insoluble Abeta were determined by using western blot techniques, and the findings were assessed in relation to indices of severity of disease. The mean level of soluble Abeta is increased threefold in Alzheimer's disease and correlates highly with markers of disease severity. In contrast, the level of insoluble Abeta (also a measure of total amyloid load) is found only to discriminate Alzheimer's disease from controls, and does not correlate with disease severity or numbers of amyloid plaques. These findings support the concept of several interacting pools of Abeta, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool. The latter may exist in both intracellular and extracellular compartments, and contain the basic forms of Abeta that cause neurodegeneration. Reducing the levels of these soluble Abeta species by threefold to levels found in normal controls might prove to be a goal of future therapeutic intervention.     

Early intraneuronal Abeta deposition in the hippocampus of APP transgenic mice

Increasing evidence suggests that intraneuronal amyloid-beta (Abeta) accumulation may be an early event in Alzheimer's disease (AD) pathogenesis. However direct in vivo evidence regarding initial Abeta seeding is missing. Using an APP transgenic mouse model, our sensitive immunocytochemical procedures revealed a novel intraneuronal Abeta deposition in the somas of hippocampal CA1/subiculum neurons far in advance of the occurrence of extracellular Abetaplaques. These deposits increased exponentially with age and were elevated approximately 4-fold (p < 0.001) by high fat/high cholesterol diet. Abeta40 and Abeta42 were the major constituents of these deposits and were co-localized with lysosomal markers. Our results are consistent with the notion that the earliest Abeta deposition occurs intraneuronally, prior to extracellular amyloid plaque formation.     

Docosahexaenoic acid stimulates non-amyloidogenic APP processing resulting in reduced Abeta levels in cellular models of Alzheimer's disease

Epidemiological studies suggest that a high intake of polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), is associated with a reduced risk of Alzheimer's disease. Here, we examined the effects of DHA on amyloid precursor protein (APP) processing in cellular models of Alzheimer's disease by analysing levels of different APP fragments, including amyloid-beta (Abeta). DHA administration stimulated non-amyloidogenic APP processing and reduced levels of Abeta, providing a mechanism for the reported beneficial effects of DHA in vivo. However, an increased level of APP intracellular domain was also observed, highlighting the need to increase our knowledge about the relevance of this fragment in Alzheimer's disease pathogenesis. In conclusion, our results suggest that the proposed protective role of DHA in Alzheimer's disease pathogenesis might be mediated by altered APP processing and Abeta production.     

Lysosomal membrane damage in soluble Abeta-mediated cell death in Alzheimer's disease

Our previous studies suggest that a failure to degrade aggregated Abeta1-42 in late endosomes or secondary lysosomes is a mechanism that contributes to intracellular accumulation in Alzheimer's disease. In this study, we demonstrate that cultured primary neurons are able to internalize soluble Abeta1-42 from the culture medium and accumulate inside the endosomal/lysosomal system. The intracellular Abeta1-42 is resistant to protease degradation and stable for at least 48 h within the cultured neurons. Incubation of cultured neurons with a cytotoxic concentration of soluble Abeta1-42 invokes the rapid free radical generation within lysosomes and disruption of lysosomal membrane proton gradient which precedes cell death. The loss of lysosomal membrane impermeability is only specific to the Abeta1-42 isoform since incubation of cells with high concentrations of Abeta1-40 has no effect on lysosomal hydrolase release. To further support the role of lysosomal membrane damage in Abeta-mediated cell death, we demonstrate that photodisruption of acridine orange (AO)-loaded lysosomes with intense blue light induces a relatively rapid synchronous lysosomal membrane damage and neuronal death similar to that observed as a result of Abeta exposure. AO leaks quickly from late endosomes and lysosomes and partially shifts the fluorescence from an orange fluorescence to a diffuse, green cytoplasmic fluorescence. Such AO relocalization is due to an initial disruption of the lysosomal proton gradient, followed by the release of lysosomal hydrolases into the cytoplasmic compartment. Treatment of cells with either the antioxidant n-propyl gallate or lysosomotropic amine (methylamine) partially blocks the release of lysosomal contents suggesting that this AO relocalization is due to lysosomal membrane oxidation. Based on these findings, we propose that the cell death mediated by the soluble Abeta may be fundamentally different from the cell loss observed following extracellular Abeta deposition.     

What is the dominant aβ species in human brain tissue? A review

Interest in the beta amyloid (Abeta) peptides continues to grow due to their known accumulation in the brains of patients with Alzheimer's disease and recent tantalising evidence that reducing such accumulations can reverse disease-associated functional deficits. Abeta peptides are naturally produced in every cell by proteolytic cleavage of the amyloid precursor protein with two main alloforms (40 or 42 amino acids) both of which are disease associated. The identification that genetic mutations causing Alzheimer's disease impact on Abeta production and clearance have allowed for the manipulation of these pathways in cellular and animal models. These studies show that the amount and type of Abeta in the brain has significant consequences on neural function. However, there have been significant difficulties in the conversion of these findings into successful treatments in humans. In this review we concentrate on data from human studies to determine any comparative differences in Abeta production and clearance that may assist with better treatment design and delivery. Abeta40 is the dominant peptide species in human cerebrospinal fluid accounting for approximately 90% of total Abeta under normal conditions. However, similar studies using disease free human brain tissue do not correlate with these findings. In these studies, concentrations of Abeta40 are low with Abeta42 often identified as the dominant species. The data suggest preferential brain tissue utilisation and/or clearance of Abeta40 compared with Abeta42, findings which may have been predicted by their physiochemical differences. In Alzheimer's disease this equilibrium is disrupted significantly increasing Abeta peptide levels in brain tissue. The disease-specific increase in Abeta40 brain tissue levels in Alzheimer's disease appears to be an important though overlooked pathological change compared with the well-documented Abeta42 change observed both in the aged and in Alzheimer's disease. These findings are discussed in association with Abeta peptide function and a model of toxicity developed.     

Early changes in neurons of the hippocampus and neocortex in transgenic rats expressing intracellular human a-beta

Alzheimer's disease (AD) studies typically focus on the extracellular impact of the amyloid-beta (Abeta) protein, however recent findings also implicate intracellular Abeta (iAbeta) accumulation in the disease's molecular neuropathology. In a double mutant transgenic rat model (AbetaPP and PS1 mutations, UKUR25), stably expressing intracellular human Abeta fragments in an environment devoid of both amyloid plaques and neurofibrillary tangles, we investigated the impact of iAbeta burden on both the incidence and relative cross sectional areas of the Golgi apparatus, lysosomes and lipofuscin bodies. Pyramidal cells within the hippocampus and neocortex of both transgenic and non-transgenic age matched controls were compared. This comparison revealed a significant increase in both the proportional area occupied by Golgi apparatus elements as well as in the mean individual cross sectional area of Golgi compartments in the hippocampus of transgenic rats as compared to controls. Elevated lysosome and lipofuscin elements in the hippocampi of transgenic rats were observed, as was an increase in the mean individual, cross sectional area of lipofuscin bodies in the cortex of transgenic rats as compared to controls. These findings support the hypothesis that intracellular Abeta accumulation not only has an impact on subcellular compartments but also potentially contributes to the neuronal cell pathology observed in AD.     

Amyloid and Alzheimer's disease: inside and out

Alzheimer's disease (AD) is poised to become the most serious healthcare issue of our generation. The leading theory of AD pathophysiology is the Amyloid Cascade Hypothesis, and clinical trials are now proceeding based on this hypothesis. Here, we review the original evidence for the Amyloid Hypothesis, which was originally focused on the extracellular deposition of beta amyloid peptides (Aβ) in large fibrillar aggregates, as well as how this theory has been extended in recent years to focus on highly toxic small soluble amyloid oligomers. We will also examine emerging evidence that Aβ may actually begin to accumulate intracellularly in lysosomes, and the role for intracellular Aβ and lysosomal dysfunction may play in AD pathophysiology. Finally, we will review the clinical implications of these findings.     

Amyloid beta-peptide levels in laser capture microdissected cornu ammonis 1 pyramidal neurons of Alzheimer's brain

Deposition of the amyloid beta-peptide (Abeta) is a pathophysiological event associated with Alzheimer's disease. Although much is known about the molecular composition of extracellular Abeta deposits, the role of the intracellular pool of Abeta is not fully understood. We investigated whether Abeta levels are increased in cornu ammonis 1 pyramidal neurons of Alzheimer's disease hippocampus, using laser capture microdissection to isolate the neurons and enzyme-linked immunosorbent assay for quantification. Our results showed increased Abeta42 levels and an elevated Abeta42/Abeta40 ratio in neurons from sporadic as well as from familial cases of Alzheimer's disease, whereas Abeta40 levels remain unchanged between the cases and controls. We speculate that intracellular accumulation of Abeta42 increase vulnerability of cornu ammonis 1 pyramidal neurons in Alzheimer's disease.     

The beta-amyloid cascade hypothesis: a sequence of events leading to neurodegeneration in Alzheimer's disease

According to the beta-amyloid cascade hypothesis, the accumulation of beta-amyloid (Abeta) deposits as amyloid plaques in the patient's brain is the primary event in the pathogenesis of Alzheimer's disease (AD). Other neuropathological changes such as neurofibrillary tangles (NFTs), synaptic degeneration and neuronal cell loss are secondary and appear as a consequence of Abeta deposition. Abeta is generated during the proteolytic processing of the beta-amyloid precursor protein (APP). The endoproteolysis of APP is catalyzed by alpha-, beta-, and gamma-secretases. The alpha-secretase pathway releases non-amyloidogenic products: sAPPbeta, p3 and C83 peptides. In the beta-secretase pathway, apart from the sAPPalpha and C99 fragments also beta-amyloid peptides: Abeta40 and/or Abeta42 are generated. Abeta42 is neurotoxic and more hydrophobic than Abeta40, thus it has stronger tendency to oligomerize and aggregate. The imbalance between Abeta production and Abeta clearance is the basis for the formation of amyloid plaques. The majority of known APP and presenilin mutations responsible for familial early onset AD affect APP processing causing overproduction of Abeta, especially Abeta42. Both extracellular and intracellular accumulation of Abeta initiates a cascade of the following events leading to the neurodegeneration: synaptic and neuritic injury, microglial and astrocytic activation (inflammatory response), altered neuronal ionic homeostasis, oxidative damages, changes of kinases/phosphatases activities, formation of NFTs, and finally cell death. In this paper, we reviewed recent findings supporting the presented hypothesis.     

Effect of cell density on intracellular levels of the Alzheimer's amyloid precursor protein

The precise function of APP (Alzheimer's amyloid precursor protein) remains to be fully elucidated, but various lines of evidence suggest that it may be involved in cell adhesion processes. Because APP is a transmembrane glycoprotein, variations in its expression level may have direct bearing on its putative role in cell adhesion. Our results revealed that although APP levels did not change markedly with increasing cell density (ICD), there was a small but reproducible increase in APP expression at subconfluent conditions. Higher expression APP levels led to corresponding increases in the amount of APP processed and secreted APP (sAPP) released into the cell media. Given that phorbol esters stimulate the non-amyloidogenic pathway at the expense of reducing production of Abeta (the peptide found deposited as neuritic plaques in the brains of patients with Alzheimer's disease), thus providing an interesting therapeutic focus, we tested the effect of the phorbol 12-myristate 13-acetate (PMA) on APP processing at ICD. PMA not only stimulated sAPP release at all densities tested, but also produced a corresponding decrease in the intracellular levels of APP. Further experimentation revealed that increased APP expression with ICD was dependent on factors present in conditioned medium. Interestingly, exposing cells to the Abeta peptide itself could mimic these results, thus providing evidence for a potential positive feedback mechanism between Abeta production and intracellular APP levels.     

Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide

Impairment of endosomal/lysosomal functions are reported as some of the earliest changes in several age-related neurological disorders such as Alzheimer's disease. Dysregulation of the lysosomal system is also accompanied by the accumulation of age-associated pigments and several recent reports have indicated that this age-related lipofuscin accumulation can sensitize cells to oxidative stress and apoptotic cell death. In this study, we have established and evaluated an in vitro age-related pathology paradigm that models lipofuscin accumulation. Our model consists of the treatment of cultured primary mouse neurons with lysosomotropic detergents. We have observed that one of the earliest biochemical changes associated with lysosomotropic detergent-induced membrane instability is a loss of the endosomal/lysosomal proton gradient integrity, followed by an activation of sphingomyelin hydrolysis and ceramide accumulation within enlarged endosomal/lysosomal vesicles. In addition, we demonstrate that ceramide accumulation correlates with the activation of proximal procaspases-8 and -9 as well as distal caspase-3, prior to the appearance of cell death. Taken together, we propose that disturbances of the endosomal/lysosomal system, in addition to the activation of the sphingomyelinase hydrolysis cycle, play essential roles in the course of post-mitotic neuronal aging. The abnormal accumulation of undigested lipids and proteins within dysfunctional endosomal/lysosomal vesicle populations during the process of pathological aging may serve as triggers of the cell death programs that are associated with downstream neurodegeneration.     

Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease.

Growing evidence suggests that mitochondrial dysfunction is one of the key intracellular lesions associated with the pathogenesis of Alzheimer's disease (AD). Mitochondria, the powerhouses of the cell, participate in a number of physiological functions that include calcium homeostasis, signal transduction, and apoptosis. However, the pathophysiological mechanisms underlying the decline of mitochondrial vital functions leading to the dysfunction of mitochondria during AD are not well understood. Recent literature has observed the accumulation of Alzheimer's amyloid precursor protein (APP) and its C-terminal-cleaved product beta-amyloid (Abeta) in the mitochondrial compartment. Furthermore, evidence also implicates that the accumulation of full-length APP and Abeta in the mitochondrial compartment has a causative role in impairing mitochondrial physiological functions. Here, we review the mode of mitochondrial transport of full-length APP and Abeta and its pathological implications in bringing about mitochondrial dysfunction as seen in AD.     

The amyloid precursor protein of Alzheimer's disease and the Abeta peptide

Alzheimer's disease is characterized by the accumulation of beta amyloid peptides in plaques and vessel walls and by the intraneuronal accumulation of paired helical filaments composed of hyperphosphorylated tau. In this review, we concentrate on the biology of amyloid precursor protein, and on the central role of amyloid in the pathogenesis of Alzheimer's disease. Amyloid precursor protein (APP) is part of a super-family of transmembrane and secreted proteins. It appears to have a number of roles, including regulation of haemostasis and mediation of neuroprotection. APP also has potentially important metal and heparin-binding properties, and the current challenge is to synthesize all these varied activities into a coherent view of its function. Cleavage of amyloid precursor protein by beta-and gamma-secretases results in the generation of the Abeta (betaA4) peptide, whereas alpha-secretase cleaves within the Abeta sequence and prevents formation from APP. Recent findings indicate that the site of gamma-secretase cleavage is critical to the development of amyloid deposits; Abeta1-42 is much more amyloidogenic than Abeta1-40. Abeta1-42 formation is favoured by mutations in the two presenilin genes (PS1 and PS2), and by the commonest amyloid precursor protein mutations. Transgenic mouse models of Alzheimer's disease incorporating various mutations in the presenilin gene now exist, and have shown amyloid accumulation and cognitive impairment. Neurofibrillary tangles have not been reproduced in these models, however. While aggregated Abeta is neurotoxic, perhaps via an oxidative mechanism, the relationship between such toxicity and neurofibrillary tangle formation remains a subject of ongoing research.     

Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease

Cell-culture studies have revealed some of the fundamental features of the interaction of amyloid Abeta with cells and the mechanism of amyloid accumulation and pathogenesis in vitro. A(beta)1-42, the longer isoform of amyloid that is preferentially concentrated in senile plaque (SP) amyloid deposits in Alzheimer's disease (AD), is resistant to degradation and accumulates as insoluble aggregates in late endosomes or lysosomes. Once these aggregates have nucleated inside the cell, they grow by the addition of aberrantly folded APP and amyloidgenic fragments of APP, that would otherwise be degraded, onto the amyloid lattice in a fashion analogous to prion replication. This accumulation of heterogeneous aggregated APP fragments and Abeta appears to mimic the pathophysiologyof dystrophic neurites, where the same spectrum of components has been identified by immunohistochemistry. In the brain, this residue appears to be released into the extracellular space, possibly by a partially apoptotic mechanism that is restricted to the distal compartments of the neuron. Ultimately, this insoluble residue may be further digested to the protease-resistant A(beta)n-42 core, perhaps by microglia, where it accumulates as senile plaques. Thus, the dystrophic neurites are likely to be the source of the immediate precursors of amyloid in the senile plaques. This is the opposite of the commonly held view that extracellular accumulation of amyloid induces dystrophic neurites. Many of the key pathological events of AD may also be directly related to the intracellular accumulation of this insoluble amyloid. The aggregated, intracellular amyloid induces the production of reactive oxygen species (ROS) and lipid peroxidation products and ultimately results in the leakage of the lysosomal membrane. The breakdown of the lysosomal membrane may be a key pathogenic event, leading to the release of heparan sulfate and lysosomal hydrolases into the cytosol. Together, these observations provide the novel view that amyloid deposits and some of the early events of amyloid pathogenesis initiate randomly within single cells in AD. This pathogenic mechanism can explain some of the more enigmatic features of Alzheimer's pathogenesis, like the focal nature of amyloid plaques, the relationship between amyloid, dystrophic neurites and neurofibrillary-tangle pathology, and the miscompartmentalization of extracellular and cytosolic components observed in AD brain.     

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.     

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.