Locus coeruleus degeneration exacerbates olfactory deficits in APP/PS1 transgenic mice

Neuronal loss in the locus coeruleus (LC) is 1 of the early pathological events in Alzheimer's disease (AD). Projections of noradrenergic neurons of the LC innervate the olfactory bulb (OB). Because olfactory deficits have been reported in early AD, we investigated the effect of induced LC degeneration on olfactory memory and discrimination in an AD mouse model. LC degeneration was induced by treating APP/PS1 mice with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4) repeatedly between 3 and 12 months of age. Short term odor retention, ability for spontaneous habituation to an odor, and spontaneous odor discrimination were assessed by behavioral tests. DSP4 treatment in APP/PS1 mice resulted in an exacerbation of short term olfactory memory deficits and more discrete weakening of olfactory discrimination abilities, suggesting that LC degeneration contributes to olfactory deficits observed in AD. Importantly, DSP4 treatment also increased amyloid β (Aβ) deposition in the olfactory bulb of APP/PS1 mice, which correlated with olfactory memory, not with discrimination deficits.     

Beta-amyloid-dependent expression of NOS2 in neurons: prevention by an alpha2-adrenergic antagonist

The neurotransmitter noradrenaline (NA) exerts important antiinflammatory effects on glial cells including suppression of the inducible form of nitric oxide synthase (NOS2). The authors examined the consequences of manipulating NA in vivo by treating adult rats with the neurotoxin DSP4, which selectively lesions noradrenergic neurons of the locus ceruleus (LC), and reduces cortical NA levels. Following LC lesion, intracortical injection of aggregated amyloid beta 1-42 (Abeta1-42) caused appearance of NOS2 within neurons, and increased neuronal damage assessed by staining for nonphosphorylated neurofilament proteins with antibody SMI-32. Co-treatment with a selective alpha2-adrenergic antagonist reduced neuronal NOS2 staining as well as SMI-32 staining. Neuronal damage was dependent on NOS2 expression since injection of Abeta1-42 into DSP4-treated NOS2-deficient mice did not result in neuronal damage. These results demonstrate that decrease of NA levels in vivo can exacerbate inflammatory responses and neuronal damage due to inflammatory stimuli such as Abeta. These findings suggest that alpha2-adrenergic antagonists could provide therapeutic benefit in neurological diseases such as AD or PD where LC loss is known to occur.     

Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes

Background

Data indicates anti-oxidant, anti-inflammatory and pro-cognitive properties of noradrenaline and analyses of post-mortem brain of Alzheimer's disease (AD) patients reveal major neuronal loss in the noradrenergic locus coeruleus (LC), the main source of CNS noradrenaline (NA). The LC has projections to brain regions vulnerable to amyloid deposition and lack of LC derived NA could play a role in the progression of neuroinflammation in AD. Previous studies reveal that intraperitoneal (IP) injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) can modulate neuroinflammation in amyloid over-expressing mice and in one study, DSP-4 exacerbated existing neurodegeneration.

Methods

TASTPM mice over-express human APP and beta amyloid protein and show age related cognitive decline and neuroinflammation. In the present studies, 5 month old C57/BL6 and TASTPM mice were injected once monthly for 6 months with a low dose of DSP-4 (5 mg kg^-1) or vehicle. At 8 and 11 months of age, mice were tested for cognitive ability and brains were examined for amyloid load and neuroinflammation.

Results

At 8 months of age there was no difference in LC tyrosine hydroxylase (TH) across all groups and cortical NA levels of TASTPM/DSP-4, WT/Vehicle and WT/DSP-4 were similar. NA levels were lowest in TASTPM/Vehicle. Messenger ribonucleic acid (mRNA) for various inflammatory markers were significantly increased in TASTPM/Vehicle compared with WT/Vehicle and by 8 months of age DSP-4 treatment modified this by reducing the levels of some of these markers in TASTPM. TASTPM/Vehicle showed increased astrocytosis and a significantly larger area of cortical amyloid plaque compared with TASTPM/DSP-4. However, by 11 months, NA levels were lowest in TASTPM/DSP-4 and there was a significant reduction in LC TH of TASTPM/DSP-4 only. Both TASTPM groups had comparable levels of amyloid, microglial activation and astrocytosis and mRNA for inflammatory markers was similar except for interleukin-1 beta which was increased by DSP-4. TASTPM mice were cognitively impaired at 8 and 11 months but DSP-4 did not modify this.

Conclusion

These data reveal that a low dose of DSP-4 can have varied effects on the modulation of amyloid plaque deposition and neuroinflammation in TASTPM mice dependent on the duration of dosing.     

Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology

Several epidemiologic studies have reported that cyclooxygenase (COX) inhibitors prevent/delay the onset of Alzheimer's disease (AD). Recent experimental studies suggest that these compounds can also diminish amyloid-beta (Abeta) neuropathology in rodent models of AD. To explore the relationship of COX expression to Abeta neuropathology, we crossed mice expressing both mutant amyloid precursor protein [K670N/M671L (APP(swe)] and mutant PS1 (A246E) with mice expressing human COX-2 selectively in neurons. We show here that human COX-2 expression in APP(swe)/PS1/COX-2 mice induces potentiation of brain parenchymal amyloid plaque formation and a greater than twofold increase in prostaglandin E2 production, at 24 months of age. This increased amyloid plaque formation coincided with a preferential elevation of Abeta1-40 and Abeta1-42 with no change in total amyloid precursor protein (APP) expression/content in the brain. Collectively these data suggest that COX-2 influences APP processing and promotes amyloidosis in the brain.     

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat

Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha₁-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in α₂-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a loss of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD.     

Noradrenergic neuromodulation in the olfactory bulb modulates odor habituation and spontaneous discrimination

Noradrenergic projections from the locus coeruleus (LC) project to the olfactory bulb (OB), a cortical structure implicated in odor learning and perceptual differentiation among similar odorants. The authors tested the role of OB noradrenaline (NA) in short-term olfactory memory using an animal model of LC degeneration coupled with intrabulbar infusions of NA. Specifically, the authors lesioned cortical noradrenergic fibers in mice with the noradrenergic neurotoxin N-Ethyl-N-(2-chloroethyl)-2-bromobenzylamine hydrochloride (DSP4) and measured the effects on an olfactory habituation/spontaneous discrimination task. DSP4-treated mice failed to habituate to repeated odor presentations, indicating that they could not remember odors over the 5-min intertrial interval. The authors then infused NA bilaterally into the OBs of both DSP4-treated and nonlesioned control animals at two concentrations (10(-3)M and 10(-5)M, 2 microl/side). In DSP4-treated animals, NA administration at either concentration restored normal habituation and spontaneous discrimination performance, indicating that noradrenergic neuromodulation mediates these aspects of perceptual learning and that its efficacy does not require activity-dependent local regulation of NA release. Functional OB learning mechanisms may be necessary for normal odor recognition and differentiation among physically similar odorants.     

Catecholaminergic neuronal loss in locus coeruleus of aged female dtg APP/PS1 mice

Alzheimer's disease (AD) is the most common type of dementia afflicting the elderly. In addition to the presence of cortical senile plaques and neurofibrillary tangles, AD is characterized at autopsy by extensive degeneration of brainstem locus coeruleus (LC) neurons that provide noradrenergic innervation to cortical neuropil, together with relative stability of dopaminergic neuron number in substantia nigra (SN) and ventral tegmental area (VTA). The present study used design-based stereological methods to assess catecholaminergic neuronal loss in brains of double transgenic female mice that co-express two human mutations associated with familial AD, amyloid precursor protein (APP_swe) and presenilin-1 (PS1_ΔE9). Mice were analyzed at two age groups, 3–6 months and 16–23 months, when deposition of AD-type β-amyloid (Aβ) plaques occurs in cortical brain regions. Blocks of brain tissue containing the noradrenergic LC nucleus and two nuclei of dopaminergic neurons, the SN and VTA, were sectioned and sampled in a systematic-random manner and immunostained for tyrosine hydroxylase (TH), a specific marker for catecholaminergic neurons. Using the optical fractionator method we found a 24% reduction in the total number of TH-positive neurons in LC with no changes in SN-VTA of aged dtg APP/PS1 mice compared with non-transgenic controls. No significant differences were observed in numbers of TH-positive neurons in LC or SN-VTA in brains of young female dtg APP/PS1 mice compared to their age-matched controls. The findings of selective neurodegeneration of LC neurons in the brains of aged female dtg APP/PS1 mice mimic the neuropathology in the brains of AD patients at autopsy. These findings support the use of murine models of Aβ deposition to develop novel strategies for the therapeutic management of patients afflicted with AD.     

Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis

The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.     

Age-dependent changes in noradrenergic locus coeruleus system in wild-type and APP23 transgenic mice

Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by the loss of neurons in specific regions of the CNS including the locus coeruleus (LC), the major noradrenergic locus in the CNS. Several animal models of AD have been developed that exhibit some of the pathophysiological changes in the CNS that are observed in AD patients. The purpose of this study was to determine if the integrity of the LC noradrenergic system is altered in the amyloid precursor protein 23 (APP23) mouse model of AD at the age of 3, 6 and 12 months through quantification of tyrosine hydroxylase (TH) mRNA expression. Despite a previous study suggesting alterations in the noradrenergic transmission system of APP23 mice, the current study failed to show altered TH-positive neuronal numbers or expression in LC noradrenergic neurons of APP23 mice versus wild-type (WT) littermates. However, the present study did demonstrate an age-dependent effect on TH mRNA expression. Both the number of TH-containing neurons and the amount of TH-positive grains/neuron significantly increased between the age of 3 and 6 months with no difference between 6 and 12 months. These observations indicate that any study comparing the noradrenergic system between WT (C57Bl/6) and experimental mice must strictly choose the age to be tested and limit age differences between control and experimental groups to the absolute minimum. More importantly, when long-term therapeutic interventions targeting the noradrenergic system are applied to mouse models, and related parameters are studied longitudinally, care should be taken to distinguish between potential therapeutic and strain-specific developmental or age-related alterations.     

Reactive astrocytes and alpha1-antichymotrypsin in Alzheimer's disease.

There is ample genetic, biochemical, cellular and molecular evidence to show that the amyloid beta peptide (Abeta), a proteolytic fragment of the amyloid precursor protein (APP), plays an important, if not causative role in Alzheimer's disease (AD). An additional hallmark of AD is the neuroinflammatory response that is associated with the amyloid deposition. We discovered that the acute phase protein alpha1-antichymotrypsin (ACT) is overexpressed by reactive astrocytes, and is tightly associated with virtually all amyloid plaques in the AD brain. It has also been shown that Abeta and ACT bind in vitro. Recently, we have reported that astrocytic expression of ACT in APP transgenic mice leads to an increased plaque deposition in ACT/APP doubly transgenic mice compared to the APP mice alone, suggesting that ACT interferes with Abeta clearance. The main objective of this review is to summarize the role of astrocytosis and ACT in the pathogenesis of AD.     

Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment

Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of Abeta42 peptide, either by increasing Abeta42 or decreasing Abeta40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G>C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the epsilon-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Abeta42 and a decrease in Abeta40 levels resulting in a near three-fold increase of the Abeta42/Abeta40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease.     

Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice

We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-beta peptide (Abeta), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Abeta, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Abeta levels and beta-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Abeta/beta-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Abeta. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40-CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion, and validate the CD40-CD40L interaction as a target for therapeutic intervention in AD.     

Antibodies from a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer’s disease

The neuropathology of Alzheimer's disease(AD) is characterized by the accumulation of amyloid peptide Abeta in the brain derived from proteolytic cleavage of the amyloid precursor protein (APP). Vaccination of mice with plasmid DNA coding for the human Abeta42 peptide together with low doses of preaggregated peptide induced antibodies with detectable titers after only 2 weeks. One serum was directed against the four aminoterminal amino acids DAEF and differs from previously described ones. Both immune sera and monoclonal antibodies solubilized preformed aggregates of Abeta42 in vitro and recognized amyloid plaques in brain sections of mice transgenic for human APP. Passive immunization of transgenic AD mice caused a significant and rapid reduction in brain amyloid plaques within 24 h. The combined DNA peptide vaccine may prove useful for active immunization with few inoculations and low peptide dose which may prevent the recently described inflammatory reactions inpatients. The monoclonal antibodies are applicable for passive immunization studies and may lead to a therapy of AD.     

The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease

Damage to noradrenergic neurons in the locus coeruleus (LC) is a hallmark of Alzheimer's disease (AD) and may contribute to disease progression. In 5xFAD transgenic mice, which accumulate amyloid burden at early ages, the LC undergoes stress as evidenced by increased astrocyte activation, neuronal hypertrophy, reduced levels of LC-enriched messenger RNAs (mRNAs), and increased inflammatory gene expression. Central nervous system (CNS) noradrenaline (NA) levels in 5-month-old male 5xFAD mice were increased using the NA precursor L-threo-3,4-dihydroxyphenylserine (L-DOPS). After 1 month, L-DOPS treatment improved learning in the Morris water maze test compared with vehicle-treated mice. L-DOPS increased CNS NA levels, and average latency times in the water maze test were inversely correlated to NA levels. L-DOPS reduced astrocyte activation and Thioflavin-S staining; increased mRNA levels of neprilysin and insulin degrading enzyme, and of several neurotrophins; and increased brain-derived neurotrophic factor protein levels. These data demonstrate the presence of LC stress in a robust mouse model of AD, and suggest that raising CNS NA levels could provide benefit in AD.     

Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition

Microglia accumulation at the site of amyloid plaques is a strong indication that microglia play a major role in Alzheimer's disease pathogenesis. However, how microglia affect amyloid-beta peptide (Abeta) deposition remains poorly understood. To address this question, we developed a novel bigenic mouse that overexpresses both amyloid precursor protein (APP) and monocyte chemotactic protein-1 (MCP-1; CCL2 in systematic nomenclature). CCL2 expression, driven by the glial fibrillary acidic protein promoter, induced mononuclear phagocyte (MP; monocyte-derived macrophage and microglial) accumulation in the brain. When APP/CCL2 transgenic mice were compared to APP mice, a fivefold increase in Abeta deposition was present despite increased MP accumulation around hippocampal and cortical amyloid plaques. Levels of full-length APP, its C-terminal fragment, and Abeta-degrading enzymes (insulin-degrading enzyme and neprilysin) in APP/CCL2 and APP mice were indistinguishable. Sodium dodecyl sulfate-insoluble Abeta (an indicator of fibrillar Abeta) was increased in APP/CCL2 mice at 5 months of age. Apolipoprotein E, which enhances Abeta deposition, was also increased (2.2-fold) in aged APP/CCL2 as compared to APP mice. We propose that although CCL2 stimulates MP accumulation, it increases Abeta deposition by reducing Abeta clearance through increased apolipoprotein E expression. Understanding the mechanisms underlying these events could be used to modulate microglial function in Alzheimer's disease and positively affect disease outcomes.     

Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways

Diversity and intensity of intellectual and physical activities seem to have an inverse relationship with the extent of cognitive decline in Alzheimer's disease (AD). To study the interaction between an active lifestyle and AD pathology, female TgCRND8 mice carrying human APPswe+ind were transferred into enriched housing. Four months of continuous and diversified environmental stimulation resulted in a significant reduction of beta-amyloid (Abeta) plaques and in a lower extent of amyloid angiopathy. Neither human amyloid precursor protein (APP) mRNA/protein levels nor the level of carboxy-terminal fragments of APP nor soluble Abeta content differed between both groups, making alterations in APP expression or processing unlikely as a cause of reduced Abeta deposition. Moreover, DNA microarray analysis revealed simultaneous down-regulation of proinflammatory genes as well as up-regulation of molecules involved in anti-inflammatory processes, proteasomal degradation, and cholesterol binding, possibly explaining reduced Abeta burden by lower aggregation and enhanced clearance of Abeta. Additionally, immunoblotting against F4/80 antigen and morphometric analysis of microglia (Mac-3) revealed significantly elevated microgliosis in the enriched brains, which suggests increased amyloid phagocytosis. In summary, this study demonstrates that the environment interacts with AD pathology at dif-ferent levels.     

Age-related amyloid beta protein accumulation induces cellular death and macrophage activation in transgenic mice

In view of the importance of amyloid beta protein accumulation in Alzheimer's disease, this paper examines age-related amyloid beta protein (Abeta) deposition and accompanying cellular changes in a mouse model in vivo. Transgenic mice were studied which expressed a gene encoding 18 residues of signal peptide and 99 residues of the carboxyl-terminal fragment (CTF) of the Abeta precursor, under the control of the cytomegalovirus enhancer/chicken beta-actin promoter. In the pancreas, Abeta accumulated in an age-dependent manner. Abeta deposits appeared as early as 3 weeks of age and increased in size and number from 4 to 16 months of age. The largest Abeta deposits were observed in the transgenic pancreas at 16 and 20 months of age. Haematoxylin and eosin staining, macrophage immunostaining, and electron microscopy showed that the Abeta fibril deposits closely correlated with degeneration of pancreatic acinar cells and macrophage activation. Abeta1-42 and Abetap3E-42 were predominant components of Abeta deposits among amino- and carboxyl-terminal modified Abeta species. These findings suggest that overproduction of Abeta causes age-related accumulation of Abeta fibrils, with accompanying cellular degeneration and macrophage activation in vivo.     

Beneficial effects of quetiapine in a transgenic mouse model of Alzheimer's disease

Previous studies have suggested that quetiapine, an atypical antipsychotic drug, may have beneficial effects on cognitive impairment, and be a neuroprotectant in treating neurodegenerative diseases. In the present study, we investigated the effects of quetiapine on memory impairment and pathological changes in an amyloid precursor protein (APP)/presenilin-1 (PS-1) double transgenic mouse model of Alzheimer's disease (AD). Non-transgenic and transgenic mice were treated with quetiapine (0, 2.5, or 5mg/(kg day)) for 1, 4, and 7 months in drinking water from the age of 2 months. After 4 and 7 months of continuous quetiapine administration, memory impairment was prevented, and the number of beta-amyloid (Abeta) plaques decreased in the cortex and hippocampus of the transgenic mice. Quetiapine also decreased brain Abeta peptides, beta-secretase activity and expression, and the level of C99 (an APP C-terminal fragment following cleavage by beta-secretase) in the transgenic mice. Furthermore, quetiapine attenuated anxiety-like behavior, up-regulated cerebral Bcl-2 protein, and decreased cerebral nitrotyrosine in the transgenic mice. These findings suggest that quetiapine can alleviate cognitive impairment and pathological changes in an APP/PS1 double transgenic mouse model of AD, and further indicate that quetiapine may have preventive effects in the treatment of AD.     

The Arctic Alzheimer mutation facilitates early intraneuronal Abeta aggregation and senile plaque formation in transgenic mice

The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (Abeta) sequence and leads to Alzheimer's disease (AD). Arctic Abeta peptides more easily form Abeta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APPArcSwe) and transgenic mice with the Swedish mutation alone (tg-APPSwe). Intense intraneuronal Abeta-immunoreactive staining was present in young tg-APPArcSwe mice, but not in tg-APPSwe mice. Intracellular Abeta aggregates in tg-APPArcSwe were strongly stained by antibodies recognizing the N-terminus of Abeta, while those recognizing the C-terminus of Abeta stained weakly. The Abeta aggregates inside neurons increased with age and predated extracellular Abeta deposition in both tg-APPArcSwe and tg-APPSwe mice. Senile plaque deposition was markedly accelerated in tg-APPArcSwe mice, as compared to tg-APPSwe mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular Abeta aggregates in association with a rapid onset of senile plaque deposition.