Amyloid-beta(1-42) rapidly forms protofibrils and oligomers by distinct pathways in low concentrations of sodium dodecylsulfate

Alzheimer's disease (AD) is characterized by large numbers of senile plaques in the brain that consist of fibrillar aggregates of 40- and 42-residue amyloid-beta (Abeta) peptides. However, the degree of dementia in AD correlates better with the concentration of soluble Abeta species assayed biochemically than with histologically determined plaque counts, and several investigators now propose that soluble aggregates of Abeta are the neurotoxic agents that cause memory deficits and neuronal loss. These endogenous aggregates are minor components in brain extracts from AD patients and transgenic mice that express human Abeta, but several species have been detected by gel electrophoresis in sodium dodecylsulfate (SDS) and isolated by size exclusion chromatography (SEC). Endogenous Abeta aggregation is stimulated at cellular interfaces rich in lipid rafts, and anionic micelles that promote Abeta aggregation in vitro may be good models of these interfaces. We previously found that micelles formed in dilute SDS (2 mM) promote Abeta(1-40) fiber formation by supporting peptide interaction on the surface of a single micelle complex. In contrast, here we report that monomeric Abeta(1-42) undergoes an immediate conversion to a predominant beta-structured conformation in 2 mM SDS which does not proceed to amyloid fibrils. The conformational change is instead rapidly followed by the near quantitative conversion of the 4 kDa monomer SDS gel band to 8-14 kDa bands consistent with dimers through tetramers. Removal of SDS by dialysis gave a shift in the predominant SDS gel bands to 30-60 kDa. While these oligomers resemble the endogenous aggregates, they are less stable. In particular, they do not elute as discrete species on SEC, and they are completed disaggregated by boiling in 1% SDS. It appears that endogenous oligomeric Abeta aggregates are stabilized by undefined processes that have not yet been incorporated into in vitro Abeta aggregation procedures.     

Interaction of human and mouse Abeta peptides

Transgenic mice over-expressing mutant human amyloid precursor protein have become an important tool for research on Alzheimer's disease (AD) and, in particular, for therapeutic screening. Many models have reported formation of amyloid plaques with age as is detected in AD. However, the plaques generated in transgenic mice are more soluble than human plaques. Differences in solubility may occur for a number of reasons; one proposal is the presence of murine Abeta peptides within the CNS milieu. Here, we report the interaction of human and murine Abeta peptides, Abeta40 and Abeta42, utilizing a fluorescence assay to monitor formation of mixed pre-fibrillar aggregates, electron microscopy to examine morphological characteristics and detergent solubility to monitor stability. Our results demonstrate that interspecies Abeta aggregates and fibres are readily formed and are more stable than homogenous human fibres. Furthermore, these results suggest that the presence of endogenous murine Abeta in human APP transgenic mice does not account for the increased solubility of plaques.     

Large aggregates are the major soluble Aβ species in AD brain fractionated with density gradient ultracentrifugation

Soluble amyloid-β (Aβ) aggregates of various sizes, ranging from dimers to large protofibrils, have been associated with neurotoxicity and synaptic dysfunction in Alzheimer's Disease (AD). To investigate the properties of biologically relevant Aβ species, brain extracts from amyloid β protein precursor (AβPP) transgenic mice and AD patients as well as synthetic Aβ preparations were separated by size under native conditions with density gradient ultracentrifugation. The fractionated samples were then analyzed with atomic force microscopy (AFM), ELISA, and MTT cell viability assay. Based on AFM appearance and immunoreactivity to our protofibril selective antibody mAb158, synthetic Aβ42 was divided in four fractions, with large aggregates in fraction 1 and the smallest species in fraction 4. Synthetic Aβ aggregates from fractions 2 and 3 proved to be most toxic in an MTT assay. In AβPP transgenic mouse brain, the most abundant soluble Aβ species were found in fraction 2 and consisted mainly of Aβ40. Also in AD brains, Aβ was mainly found in fraction 2 but primarily as Aβ42. All biologically derived Aβ from fraction 2 was immunologically discriminated from smaller species with mAb158. Thus, the predominant species of biologically derived soluble Aβ, natively separated by density gradient ultracentrifugation, were found to match the size of the neurotoxic, 80-500 kDa synthetic Aβ protofibrils and were equally detected with mAb158.     

Tissue Transglutaminase and Its Product Isopeptide Are Increased in Alzheimer’s Disease and APPswe/PS1dE9 Double Transgenic Mice Brains

Alzheimer’s disease (AD) is characterized by intracellular and extracellular protein aggregates, including microtubule-associated protein tau and cleavage product of amyloid precursor protein, β-amyloid (Aβ). Tissue transglutaminase (tTG) is a calcium-dependent enzyme that cross-links proteins forming a γ-glutamyl-ε-lysine isopeptide bond. Highly resistant to proteolysis, this bond can induce protein aggregation and deposition. We set out to determine if tTG may play a role in pathogenesis of AD. Previous studies have shown that tTG and isopeptide are increased in advanced AD, but they have not addressed if this is an early or late feature of AD. In the present study, we measured tTG expression levels and enzyme activity in the brains of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD, as well as a transgenic mouse model of AD. We found that both enzyme expression and activity were increased in MCI as well as AD compared to NCI. In the transgenic model of AD, tTG expression and enzyme activity increased sharply with age and were relatively specific for the hippocampus. We also assessed overlap of isopeptide immunoreactivity with neurodegeneration-related proteins with Western blots and found neurofilament, tau, and Aβ showed co-localization with isopeptide in both AD and transgenic mice. These results suggest that tTG might be a key factor in pathogenesis of abnormal protein aggregation in AD.     

Time sequence of oxidative stress in the brain from transgenic mouse models of Alzheimer's disease related to the amyloid-β cascade

Alzheimer's disease (AD) is a multifactorial disorder characterized by the presence of amyloid plaques and neurofibrillary tangles (NFTs). Rare early-onset forms of AD are associated with autosomal dominant mutations in the amyloid precursor protein gene, presenilin 1 gene, or presenilin 2 gene. The late-onset form of the disease (LOAD) is the most common form. The causes of LOAD are not yet clarified, but several environmental and genetic risk factors have been identified. Numerous studies have highlighted a role for free radical-mediated injury to brain regions of this illness. In addition, studies from mild cognitive impairment patients suggest that oxidative stress is an early event in the pathogenesis of AD. The associations between these markers of free radical damage and the pathogenic cascades involved in AD are complex. Over the past 2 decades, a number of mouse models have been created to recapitulate the major neuropathological hallmarks of AD, namely amyloid plaques and NFTs. These mice recapitulate many, although not all, of the key features of AD. Some strains of transgenic mice develop amyloid plaques, some accumulate NFTs, and some do both. Here we review the evidence for increased free radical-mediated damage to the brain with particular attention to the stage of the disease in various transgenic models of AD related to the amyloid-β cascade.     

Processing of neuropeptide Y, galanin, and somatostatin in the cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two prevalent neurodegenerative disorders for which the causes are unknown, except in rare familial cases. Several changes in neuropeptide levels as measured by radioimmunoassay (RIA) have been observed in these illnesses. Somatostatin (SOM) levels in cerebrospinal fluid (CSF) are consistently decreased in AD and FTD. Neuropeptide Y (NPY) levels are decreased in AD, but normal in FTD. Galanin (GAL) levels increase with the duration of illness in AD patients. The majority of studies of neuropeptides in CSF have not been verified by HPLC. The observed decrease in a neuropeptide level as measured by RIA may therefore reflect an altered synthesis or extracellular processing, resulting in neuropeptide fragments that may or may not be detected by RIA. Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-MS) has been shown to be a powerful technique in the analysis of biological materials without any pre-treatment, by detecting peptides and proteins at a specific mass-to-charge (m/z) ratio. We studied the processing of the neuropeptides NPY, NPY, SOM and GAL in the cerebrospinal fluid of patients with AD (n = 3), FTD (n = 3) and controls (n = 2) using MALDI-MS. We found that considerable inter-individual variability exists in the rate of neuropeptide metabolism in CSF, as well as the number of peptide fragments formed. Certain patients showed differences in the processing of specific neuropeptides, relative to other patients and controls. This analysis of the metabolic processing of neuropeptides in CSF yielded a large amount of data for each individual studied. Further studies are required to determine the changes in neuropeptide processing that can be associated with AD and FTD. With further investigations using MALDI-MS analysis, it may be possible to identify a neuropeptide fragment or processing enzyme that can be correlated to these disease states.     

APP transgenic mice Tg2576 accumulate Abeta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques.

The amyloid (Abeta) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice are physically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenic mouse Abeta peptides were purified using sequential size-exclusion and reverse-phase chromatographic systems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse Abeta peptides lacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundant in the stable Abeta peptide deposits observed in AD. Truncated Abeta molecules appear to be generated in vivo by hydrolysis at multiple sites rather than by post-mortem C-terminal degradation. In contrast to AD amyloid cores, the Tg mice peptides were soluble in Tris-SDS-EDTA solutions, revealing both monomeric and SDS-stable oligomeric species of Abeta. In contrast to our report on Novartis Pharma APP23 Tg mice [Kuo et al. (2001) J. Biol. Chem. 276, 12991], which maintain high levels of soluble Abeta early on with later development of extensive vascular amyloid, Tg2576 mice exhibited an age-related elevation of soluble Abeta with relatively limited vascular amyloid deposition. The transgenic mouse levels of carboxy-terminal (CT) APP fragments were nearly 10-fold greater than those of human brains, and this condition may contribute to the unique pathology observed in these animals. Immunization of transgenic mice may act to prevent the pathological effects of betaAPP overproduction by binding CT molecules or halting their processing to toxic forms, in addition to having any effects on Abeta itself. Thus, differences in disease evolution and biochemistry must be considered when using transgenic animals to evaluate drugs or therapeutic interventions intended to reduce the Abeta burden in Alzheimer's disease.     

Behavioral assessment of Alzheimer's transgenic mice following long-term Abeta vaccination: task specificity and correlations between Abeta deposition and spatial memory.

Long-term vaccinations with human beta-amyloid peptide 1-42 (Abeta1-42) have recently been shown to prevent or markedly reduce Abeta deposition in the PDAPP transgenic model of Alzheimer's disease (AD). Using a similar protocol to vaccinate 7.5-month-old APP (Tg2576) and APP+PS1 transgenic mice over an 8-month period, we previously reported modest reductions in brain Abeta deposition at 16 months. In these same mice, Abeta vaccinations had no deleterious behavioral effects and, in fact, benefited the mice by providing partial protection from age-related deficits in spatial working memory in the radial arm water maze task (RAWM) at 15.5 months. By contrast, control-vaccinated transgenic mice exhibited impaired performance throughout the entire RAWM test period at 15.5 months. The present study expands on our initial report by presenting additional behavioral results following long-term Abeta vaccination, as well as correlational analyses between cognitive performance and Abeta deposition in vaccinated animals. We report that 8 months of Abeta vaccinations did not reverse an early-onset balance beam impairment in transgenic mice. Additionally, in Y-maze testing at 16 months, all mice showed comparable spontaneous alternation irrespective of genotype or vaccination status. Strong correlations were nonetheless present between RAWM performance and extent of "compact" Abeta deposition in both the hippocampus and the frontal cortex of vaccinated APP+PS1 mice. Our results suggest that the behavioral protection of long-term Abeta vaccinations is task specific, with preservation of hippocampal-associated working memory tasks most likely to occur. In view of the early short-term memory deficits exhibited by AD patients, Abeta vaccination of presymptomatic AD patients could be an effective therapeutic to protect against such cognitive impairments.     

Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic mice

The neuropathological hallmark shared between Alzheimer's disease (AD) and familial frontotemporal dementia (FTDP-17) are neurofibrillary tangles (NFT) which are composed of filamentous aggregates of the microtubule-associated protein tau. Their formation has been reproduced in transgenic mice, which express the FTDP-17-associated mutation P301L of tau. In these mice, tau aggregates are found in many brain areas including the hippocampus and the amygdala, both of which are characterized by NFT formation in AD. Previous studies using an amygdala-specific test battery revealed an increase in exploratory behavior and an accelerated extinction of conditioned taste aversion in these mice. Here, we assessed P301L mice in behavioral tests known to depend on an intact hippocampus. Morris water maze and Y-maze revealed intact spatial working memory but impairment in spatial reference memory at 6 and 11 months of age. In addition, a modest disinhibition of exploratory behavior at 6 months of age was confirmed in the open field and the elevated O-maze and was more pronounced during aging.     

Signal transduction in Alzheimer disease: p21-activated kinase signaling requires C-terminal cleavage of APP at Asp664

The deficits in Alzheimer disease (AD) stem at least partly from neurotoxic β-amyloid peptides generated from the amyloid precursor protein (APP). APP may also be cleaved intracellularly at Asp664 to yield a second neurotoxic peptide, C31. Previously, we showed that cleavage of APP at the C-terminus is required for the impairments seen in APP transgenic mice, by comparing elements of the disease in animals modeling AD, with (platelet-derived growth factor B-chain promoter-driven APP transgenic mice; PDAPP) versus without (PDAPP D664A) a functional Asp664 caspase cleavage site. However, the signaling mechanism(s) by which Asp664 contributes to these deficits remains to be elucidated. In this study, we identify a kinase protein, recently shown to bind APP at the C-terminus and to contribute to AD, whose activity is modified in PDAPP mice, but normalized in PDAPP D664A mice. Specifically, we observed a significant increase in nuclear p21-activated kinase (isoforms 1, 2, and or 3; PAK-1/2/3) activation in hippocampus of 3 month old PDAPP mice compared with non-transgenic littermates, an effect completely prevented in PDAPP D664A mice. In contrast, 13 month old PDAPP mice displayed a significant decrease in PAK-1/2/3 activity, which was once again absent in PDAPP D664A mice. Similarly, in hippocampus of early and severe AD subjects, there was a progressive and subcellular-specific reduction in active PAK-1/2/3 compared with normal controls. Interestingly, total PAK-1/2/3 protein was increased in early AD subjects, but declined in moderate AD and declined further, to significantly below that of control levels, in severe AD. These findings are compatible with previous suggestions that PAK may be involved in the pathophysiology of AD, and demonstrate that both early activation and late inactivation in the murine AD model require the cleavage of APP at Asp664.     

Transmission of pathogenic protein aggregates in Alzheimer’s disease

Deposits of amyloid peptide Aβ and intracellular aggregates of hyperphosphorylated tau protein in the brain of patients are major neuropathological features of Alzheimer’s disease (AD). For a long time, the possibility of horizontal transmission of Aβ aggregates from cell to cell and from person to person remained hypothetical, since there was no experimental evidence. However, in 1993, the formation of senile plaques was confirmed in the brains of animals after intracerebral injections of AD patient brain homogenates. or homogenates of the brain of transgenic mice enriched with Aβ aggregates Other experiments indicate that amyloid peptide Aβ and intracellular aggregates of hyperphosphorylated tau protein may be transferred from cell to cell like prions. In 2015 and 2016, it was reported that AD could be transmitted to humans during medical procedures, i.e., that this disease might be iatrogenic. This review discusses the mechanisms by which pathogenic Aβ protein can be transmitted between cells and analyzes the current evidence concerning the possibility of horizontal Aβ transmission from person to person.     

A mini review: Tau transgenic mouse models and olfactory dysfunction in Alzheimer's Disease

Alzheimer's Disease(AD) is a chronic neurodegenerative disease that usually takes many years from preclinical phase to prodromal phase characterized by mild symptoms before the onset of dementia. Once diagnosed with AD, the brain is already severely damaged and the disease will process quickly to the most severe stages since there is no medications that reverse the neuronal injuries in the brain. Thus, simple, inexpensive, and widely available methods for detecting potential AD patients during their preclinical phases are urgently needed. In such case, olfactory testing may offer a chance for early diagnosis of AD. However, there are limitations in these olfactory tests due to the complexity of the brain areas it extends to and the frequently olfactory fatigue occurred in the behavioral olfactory tests. Great efforts have been done epidemiologically to investigate the correlation between olfactory functions and possibility of developing AD. Different patterns of olfactory dysfunction have been found in AD at early stages and even mild cognitive impairment(MIC), but the cause of the dysfunction remained unclear. Various kinds of AD animal models have been used in the field to clarify the existence of olfactory dysfunctions and thus study the underling mechanism of the dysfunction. In this review we discuss(1) the function of Tau physiologically and pathologically;(2) the genetic background and biological characteristics of the most commonly used Tau transgenic mice;(3) the structural and molecule basis of olfaction;(4) the possible relationship between Tau pathology and olfactory dysfunction. Finally, we suggest that the tau transgenic mouse models may be helpful in studying the possible mechanisms of the dysfunction.     

Alzheimer's disease: Abeta, tau and synaptic dysfunction

Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by two hallmark lesions: extracellular amyloid plaques and neurofibrillary tangles. The role that these lesions have in the pathogenesis of AD has proven difficult to unravel, in part because of unanticipated challenges of reproducing both pathologic hallmarks in transgenic mice. Recent advances in recapitulating both plaques and tangles in the brains of transgenic mice are leading to novel insights into their role in the degenerative process, including their impact on synaptic activity and plasticity. Transgenic mice that harbor both neuropathological lesions are also facilitating the elucidation of the relationship of these proteinaceous aggregates to one another and providing a crucial in vivo system for developing and evaluating therapies.     

Modulation of Aβ peptides by estrogen in mouse models

Clinical studies have shown that estrogen deprivation through menopause is a risk factor in both the initiation and progression of Alzheimer's disease (AD) and that estrogen replacement therapy may be protective. One of the major pathological features in the human AD brain is the senile plaque, a proteinaceous structure composed mainly of heterogeneous peptides collectively known as A-beta (A(beta)). In vitro studies have linked estrogen with A(beta) modulation, suggesting that one-way that estrogen depletion at menopause may exacerbate the features of AD is through A(beta) accumulation. To test this, two studies were performed on transgenic models of amyloidosis. Firstly, transgenic mice without detectable amyloid aggregates were subjected to ovariectomy and estradiol supplementation, and A(beta) levels were assessed. Secondly, the effects of estrogen modulation were assessed in mice at an age when plaques would be forming initially. Overall, A(beta) levels were higher in estrogen-deprived mice than intact mice, and this effect could be reversed through the administration of estradiol. These data suggest that, in vivo, estrogen depletion leads to the accumulation of A(beta) in the CNS, which can be reversed through replacement of estradiol. These results provide evidence that post-menopausal estrogen depletion may be linked to an increased risk of AD through A(beta) modulation.     

Altered glycosylation of acetylcholinesterase in APP (SW) Tg2576 transgenic mice occurs prior to amyloid plaque deposition

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

Transgenic rice expressing amyloid β-peptide for oral immunization

Various vaccine therapies for Alzheimer's disease (AD) have been investigated. Here we report transgenic rice expressing amyloid β-peptide (Aβ). The Aβ42 gene fused with a green fluorescent protein gene was introduced into rice using the Agrobacterium method. When transgenic brown rice expressing Aβ was orally administered to mice, serum anti-Aβ antibody titers were elevated. The same results were observed when mice were fed boiled, transgenic brown rice. The results indicate that an edible vaccine against AD using rice may be feasible. A vaccine derived from rice would be far cheaper than existing medical vaccines.     

Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease

Increased levels of a 40-42 amino-acid peptide called the amyloid beta protein (A beta) and evidence of oxidative damage are early neuropathological markers of Alzheimer's disease (AD). Previous investigations have demonstrated that melatonin is decreased during the aging process and that patients with AD have more profound reductions of this hormone. It has also been recently shown that melatonin protects neuronal cells from A beta-mediated oxidative damage and inhibits the formation of amyloid fibrils in vitro. However, a direct relationship between melatonin and the biochemical pathology of AD had not been demonstrated. We used a transgenic mouse model of Alzheimer's amyloidosis and monitored over time the effects of administering melatonin on brain levels of A beta, abnormal protein nitration, and survival of the mice. We report here that administration of melatonin partially inhibited the expected time-dependent elevation of beta-amyloid, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice. These findings may bear relevance to the pathogenesis and therapy of AD.     

Immunotherapeutic strategies for prevention and treatment of Alzheimer's disease.

Pathologic examination in Alzheimer's disease (AD) shows a significant correlation between beta-amyloid peptide (AbetaP) deposition and the clinical severity of dementia. Formation of beta-amyloid (Abeta) is a complex kinetic and thermodynamic process, dependent on peptide-peptide interactions that may be modulated by other proteins. We found that site-directed antibodies toward peptide EFRH sequences 3-6 of the N-terminal region of AbetaP suppress in vitro formation of Abeta and dissolve already-formed fibrillar amyloid. These so-called chaperone-like properties of monoclonal antibodies led to the development of a new immunologic approach to AD treatment. The immunization procedure, based on phages displaying the EFRH epitope as antigen, induced anti-AbetaP antibodies that recognized the whole AbetaP and exhibited antiaggregating properties similar to those of antibodies obtained by injection of Abeta fibrils. Production and performance of anti-beta-amyloid antibodies in the transgenic mouse model of AD showed that these antibodies may be delivered from the periphery to the central nervous system, preventing the formation of Abeta and dissolving already-present aggregates. Moreover, immunization with Abeta protected transgenic mice from the learning and age-related memory deficits that occur in AD. These data support the hypotheses that Abeta plays a central role in AD and that site-directed antibodies that modulate Abeta conformation may provide immunotherapy of the disease.     

APP transgenic mice and their application to drug discovery

The development of transgenic mice expressing mutated forms of the human amyloid precursor protein (APP) and presenilin-1 (PS1), proteins associated with familial forms of Alzheimer's disease (AD), has provided a backbone for translational studies of potential novel drug therapies. Such mice model some aspects of AD pathology in that they develop senile plaque-like deposits of the amyloid beta-protein (Aβ) together with inflammatory pathology and some degree of neurodegeneration. Aβ deposition is considered to be a potentially pathogenic feature of AD and drug discovery programmes utilising such mice and associated with drugs now reaching the clinic have been largely directed towards decreasing the deposition. This goal has been achieved in the mouse models, although the agents developed have not, to date, shown evidence of efficacy in AD sufferers and, in some cases, have worsened the clinical state. Nevertheless, reducing the pathological features of the disease continues to be the objective of pharmacological intervention and ongoing programmes continue to use transgenic mice expressing mutated APP and PS1 transgenes in attempts to overcome issues and difficulties arising from the initial clinical trials and to explore new approaches to AD treatment.     

Beta-amyloid treatment of two complementary P301L tau-expressing Alzheimer's disease models reveals similar deregulated cellular processes

Alzheimer's disease (AD) is characterized by Abeta peptide-containing plaques and tau-containing neurofibrillary tangles (NFTs). Both pathologies have been combined by crossing Abeta plaque-forming APP mutant mice with NFT-forming P301L tau mutant mice or by stereotaxically injecting beta-amyloid peptide 1-42 (Abeta42) into brains of P301L tau mutant mice. In cell culture, Abeta42 induces filamentous tau aggregates. To understand which processes are disrupted by Abeta42 in the presence of tau aggregates, we applied comparative proteomics to Abeta42-treated P301L tau-expressing neuroblastoma cells and the amygdala of P301L tau transgenic mice stereotaxically injected with Abeta42. Remarkably, a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. We also identified model-specific effects of Abeta42 treatment such as differences in cell signaling proteins in the cellular model and of cytoskeletal and synapse associated proteins in the amygdala. By Western blotting (WB) and immunohistochemistry (IHC), we were able to show that 72% of the tested candidates were altered in human AD brain with a major emphasis on stress-related unfolded protein responsive candidates. These data highlight these processes as potentially important initiators in the Abeta42-mediated pathogenic cascade in AD and further support the role of unfolded proteins in the course of AD.