The Arctic amyloid-β precursor protein (AβPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aβ

The Arctic (p. E693G) mutation in the amyloid-β precursor protein (AβPP) facilitates amyloid-β (Aβ) protofibril formation and generates clinical symptoms of Alzheimer's disease (AD). Here, molecular details of Aβ in post mortem brain were investigated with biochemical and morphological techniques. The basic structure of Arctic plaques resembled cotton wool plaques. However, they appeared ring-formed with Aβ42-specific antibodies, but were actually targetoid, since the periphery and center of many parenchymal Aβ deposits stained differently with mid-domain, N- and C-terminal Aβ antibodies. Aβ fibrils were similar in shape, albeit shorter than in sporadic AD brain, when examined by electron microscopy. Aβwild-type and Aβarctic codeposited and parenchymal deposits were highly enriched in both N- and C-terminally truncated Aβ. In contrast, cerebral amyloid angiopathy (CAA) contained a substantial amount of Aβ1-40. The absence of plaques with cores of fibrillary Aβ might be due to the scarcity of full-length Aβ, although other mechanisms could be involved. Our findings are discussed in relation to mechanisms and relevance of amyloid formation and to the clinical features of AD.     

Upregulation of tPA/plasminogen proteolytic system in the periphery of amyloid deposits in the Tg2576 mouse model of Alzheimer's disease

Although the tissue plasminogen activator (tPA)/plasminogen/plasmin proteolytic system is thought to modulate the catabolism of amyloid-β (Aβ), in vivo evidence remains insufficient. In the brain of human amyloid precursor protein transgenic Tg2576 mice, we found co-accumulation of tPA and plasminogen at the periphery of compact amyloid deposits, mainly Aβ42-cored plaques, as well as in the walls of blood vessels with cerebral amyloid angiopathy (CAA). This tPA/plasminogen system contained high levels of proteolytic activity. High levels of tPA were also found in reactive astrocytes with increased Aβ42 expression, whereas plasminogen was found only in neurons. When the brain sections of Tg2576 mice were treated with both tPA and plasminogen, levels of thioflavin-S fluorescence, congophilicity and birefringence in the compact amyloid plaques were significantly reduced, and the ultrastructure of Aβ42-fibrils was disrupted. These results suggest that the assembled Aβ42 may promote upregulation of the tPA/plasminogen proteolytic system, which can modulate the deposition of amyloid plaques in vivo.     

Fractal analysis of amyloid plaques in Alzheimer's disease patients and mouse models

The varied morphological and biochemical forms in which amyloid deposits in brain of Alzheimer's disease (AD) patients are complex and their mechanisms of formation are not completely understood. Here we investigated the ability of fractal dimension (FD) to differentiate between the textures of commonly observed amyloid plaques in sporadic and familial AD patients and aged-control individuals as well as in transgenic mouse models of amyloidosis. Studying more than 6000 amyloid plaques immunostained for total Aβ (Aβt), Aβ40 or Aβ42, we show here that Aβ40 FD could efficiently differentiate between (i) AD patients and aged-control individuals (P < 0.001); (ii) sporadic and familial AD due to presenilin-1 or APP (A692G) mutations (P < 0.001); and (iii) three transgenic mouse models of different genotypes (P < 0.001). Furthermore, while diffuse and dense-core plaques present in humans and transgenic mice had comparable FDs, both Aβt and Aβ42 FD could also differentiate diffuse plaques from other plaque types in both species (P < 0.001). Our data suggest that plaque FD could be a valuable tool for objective, computer-oriented AD diagnosis as well as for genotype-phenotype correlations of AD.     

Baicalin prevents the production of hydrogen peroxide and oxidative stress induced by Aβ aggregation in SH-SY5Y cells

Alzheimer's disease (AD) is a common form of neurodegenerative disease. Mounting evidence suggests that metal ions play a key role in the aggregation of amyloid β peptide (Aβ), which acts as a factor or cofactor in the etiopathogenesis of AD. Therefore, inhibition of Aβ aggregation emerges as a potential approach for the treatment of AD. We have found that baicalin can interact with copper directly and inhibits Aβ1–42 aggregation. In addition, baicalin protects SH-SY5Y cells from oxidative injuries induced by Aβ1–42 aggregation through decreasing H₂O₂ production that is normally formed as a deleterious by-product of beta amyloid aggregation and the formation of plaques. Taken together, these data indicate that baicalin may be a potential agent to inhibit Aβ aggregation and thereby delay, mitigate or modify the progression of neurodegenerative diseases such as AD.     

Tissue plasminogen activator arrests Alzheimer's disease pathogenesis

The progressive deposition of amyloid-β (Aβ) in the brain is a pathologic feature of Alzheimer's disease (AD). This study was aimed to determine whether endogenous tissue plasminogen activator (tPA) modulates the pathogenic process of AD. tPA expression and activity developed around amyloid plaques in the brains of human amyloid precursor protein–overexpressing Tg2576 mice, which were weakened by the genetic ablation of tPA. Although the complete loss of tPA was developmentally fatal to Tg2576 mice, tPA-heterozygous Tg2576 mice expressed the more severe degenerative phenotypes than tPA wild-type Tg2576 mice, including abnormal and unhealthy growth, shorter life spans, significantly enhanced Aβ levels, and the deposition of more and larger amyloid plaques in the brain. In addition, the expression of synaptic function–associated proteins was significantly reduced, which in turn caused a more severe impairment in learning and memory performance in Tg2576 mice. Thus, endogenous tPA, preferentially its aggregate form, could degrade Aβ molecules and maintain low levels of brain Aβ, resulting in the delay of AD pathogenesis.     

Cerebral Amyloid β Protein Deposits and Other Alzheimer Lesions in Non-Demented Elderly East Africans

There is little knowledge of the existence of Alzheimer disease (AD) or Alzheimer type of dementia in indigenous populations of developing countries. In an effort to evaluate this, we assessed the deposition of amyloid β (Aβ) protein and other lesions associated with AD in brains of elderly East Africans. Brain tissues were examined from 32 subjects, aged 45 to 83 years with no apparent neurological disease, who came to autopsy at two medical Institutions in Nairobi and Dar es Salaam. An age-matched sample from subjects who had died from similar causes in Cleveland was assessed in parallel. Of the 20 samples from Nairobi, 3 (15%) brains exhibited neocortical Aβ deposits that varied from numerous diffuse to highly localized compact or neuritic plaques, many of which were also thioflavin S positive. Two of the cases had profound AS deposition in the prefrontal and temporal cortices and one of these also exhibited moderate to severe cerebral amyloid angiopathy. Similarly, 2 of the 12 samples from Dar es Salaam exhibited diffuse and compact Aβ deposits that were also predominantly reactive for the longer Aβ₄₂ species compared to Aβ₄₀. We also noted that Aβ plaques were variably immunoreactive for amyloid associated proteins, apolipoprotein E, serum amyloid P and complement C3. Tau protein reactive neurofibrillary tangles (NFT) were also evident in the hippocampus of 4 subjects. By comparison, 4 (20%) of the 20 samples from randomly selected autopsies performed in Cleveland showed Aβ deposits within diffuse and compact parenchymal plaques and the vasculature. These observations suggest Aβ deposition and some NFT in brains of non-demented East Africans are qualitatively and quantitatively similar to that in age-matched elderly controls from Cleveland. While our small scale study does not document similar prevalence rates of preclinical AD, it suggests that elderly East Africans are unlikely to escape AD as it is known in developed countries.     

Immunohistochemical detection of the delayed formation of nonfibrillar large amyloid‐β aggregates

The occurrence of senile plaques consisting of amyloid‐β protein (Aβ) is a major neuropathological hallmark of Alzheimer's disease (AD). We previously developed and characterized monoclonal antibodies 31‐2 and 75‐2 that specifically bind to nonfibrillar Aβ_1–42 aggregates with diameters of more than 220 and 50 nm, respectively. Here, we report the use of these antibodies to examine the aggregation of exogenous Aβ_1–42 in cultured rat hippocampal neurons. From 6 to 24 h after transfection of Aβ_1–42, antibody 75‐2 immunolabeled almost all transfected neurons, whereas 31‐2‐positive cells were restricted to a part of the transfected neurons and gradually increased in number. Expression of the F19S/L34P‐mutant Aβ_1–42, which showed less of a tendency to aggregate, resulted in clearly reduced immunoreactivity to both antibodies. We also immunohistochemically investigated the temporal cortices of patients with AD and found that 31‐2 preferentially labeled the cores of a subpopulation of large amyloid plaques. The relative number of 31‐2‐immunoreactive plaques was found to correlate with the Braak stages of neurofibrillary tangles, but not with that of amyloid plaques. These results suggest that 31‐2‐reactive Aβ aggregates develop with a delayed time course in cultured neurons and amyloid plaques of AD brains.     

Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease

The presenilins (PSs) are components of large molecular complexes that contain beta-catenin and function as gamma-secretase. We report here a striking correlation between amyloid angiopathy and the location of mutation in PS-1 linked Alzheimer's disease. The amount of amyloid beta protein, Abeta(42(43)), but not Abeta(40,) deposited in the frontal cortex of the brain is increased in 54 cases of early-onset familial Alzheimer's disease, encompassing 25 mutations in the presenilin-1 (PS-1) gene, compared to sporadic Alzheimer's disease. The amount of Abeta(40) in PS-1 Alzheimer's disease varied according to the copy number of epsilon4 alleles of the Apolipoprotein E gene. Although the amounts of Abeta(40) and Abeta(42(43)) deposited did not correlate with the genetic location of the mutation in a strict linear sense, the histological profile did so vary. Cases with mutations between codon 1 and 200 showed, in frontal cortex, many diffuse plaques, few cored plaques, and mild or moderate amyloid angiopathy. Cases with mutations occurring after codon 200 also showed many diffuse plaques, but the number and size of cored plaques were increased (even when epsilon4 allele was not present) and these were often clustered around blood vessels severely affected by amyloid angiopathy. Similarly, diverging histological profiles, mainly according to the degree of amyloid angiopathy, were seen in the cerebellum. Mutations in the PS-1 gene may therefore alter the topology of the PS-1 protein so as to favor Abeta formation and deposition, generally, but also to facilitate amyloid angiopathy particularly in cases in which the mutation lies beyond codon 200. Finally we report that the amount of Abeta(42(43)) deposited in the brain correlated with the amount of this produced in culture by cells bearing the equivalent mutations.     

Histochemical analysis of senile plaque amyloid and amyloid angiopathy

Summary Histochemical methods were used to obtain information on the chemical constituents of brain amyloid in senile dementia of the Alzheimer type. The staining properties of brain amyloid (senile plaque and amyloid angiopathy) were compared with those of extraneural amyloidosis and endocrine amyloid. We found no histochemical differences between amyloid in senile plaques and in amyloid angiopathy. The content of aromatic amino acids was higher in amyloid of plaques and in amyloid angiopathy than in endocrine amyloid. Furthermore, we found persistent birefringence and affinity of brain amyloid for Congo red after exposure to potassium permanganate, suggesting that AA amyloid is not a major constituent of cerebral amyloid.     

Synaptic transmission is impaired prior to plaque formation in amyloid precursor protein–overexpressing mice without altering behaviorally-correlated sharp wave–ripple complexes

One of the hallmarks of Alzheimer's disease is the accumulation of amyloid plaques in brains of affected patients. Several recent studies provided evidence that soluble oligomer forms of amyloid-β (Aβ) rather than plaques determine cognitive decline. In vitro studies using artificial Aβ oligomer preparations suggest that such pathophysiology is caused by a specific impairment of synaptic function. We examined whether synaptic deficits occur before deposition of insoluble fibrillar Aβ by analyzing brain slices taken from young Tg2576 mice overexpressing mutant amyloid precursor protein. Excitatory synaptic transmission in the hippocampal CA1 region was strongly impaired before plaque development, suggesting a dissociation of an early synaptic impairment, probably caused by soluble oligomeric amyloid-β, from subsequent plaque formation. At higher age neurotransmission was also decreased in wild type mice, paralleling a cognitive decline of normal aged animals. Memory formation in rats is accompanied by distinct hippocampal network oscillations. It has recently been shown that hippocampal gamma oscillations, a network correlate of exploratory behavior, are impaired in amyloid precursor protein (APP)–overexpressing mice. We determined whether sharp wave–ripple complexes, which contribute to memory consolidation during slow wave-sleep, are modified in Tg2576 mice. Interestingly, neither sharp waves nor superimposed ripples were changed at pre-plaque or plaque stages. During aging, however, there was a strong reduction of sharp wave frequency and ripple energy in wild type and APP-overexpressing animals. This indicates that the reported changes in network oscillations following APP-overexpression are specific for gamma oscillations, whereas aging has a more general effect on network properties. Taken together our data suggest that non-fibrillar forms of Aβ—possibly Aβ oligomers—specifically interfere with synaptic function in Tg2576, but do not globally alter memory-related network properties. We propose that mechanisms leading to Aβ-related cognitive decline are different from those related to aging.     

Pyroglutamate-Aβ 3 and 11 colocalize in amyloid plaques in Alzheimer's disease cerebral cortex with pyroglutamate-Aβ 11 forming the central core

N-terminal truncated amyloid beta (Aβ) derivatives, especially the forms having pyroglutamate at the 3 position (AβpE3) or at the 11 position (AβpE11) have become the topic of considerable study. AβpE3 is known to make up a substantial portion of the Aβ species in senile plaques while AβpE11 has received less attention. We have generated very specific polyclonal antibodies against both species. Each antibody recognizes only the antigen against which it was generated on Western blots and neither recognizes full length Aβ. Both anti-AβpE3 and anti-AβpE11 stain senile plaques specifically in Alzheimer's disease cerebral cortex and colocalize with Aβ, as shown by confocal microscopy. In a majority of plaques examined, AβpE11 was observed to be the dominant form in the innermost core. These data suggest that AβpE11 may serve as a generating site for senile plaque formation.     

Detection of Aβ Plaques by a Novel Specific MRI Probe Precursor CR‐BSA‐(Gd‐DTPA)n in APP/PS1 Transgenic Mice

Amyloid plaques are one of the hallmarks of Alzheimer's disease (AD). The lack of specific probes that can detect individual senile plaques in AD has prompted the development of magnetic resonance imaging (MRI) probes. In this study, based on DTPA‐gadolinium (III) and congo red (CR), a novel specific MRI probe precursor CR‐BSA‐(Gd‐DTPA)n was successfully synthesized. Its ability to bind to amyloid plaques was evaluated by brain sections from APP/PS1 transgenic mice. Its specificity for Aβ plaques was further demonstrated by immunohistochemistry (IHC) staining with the monoclonal antibody to the Aβ protein. Meanwhile, the amyloid deposits detected by the CR‐BSA‐(Gd‐DTPA)n were matched to the amyloid deposits detected by Aβ specific antibody. We also found that a few amyloid‐like deposits which was not detected by IHC. The findings indicated that the probe perhaps could detect the neurofibrillary tangles (NFT) similar to the effect of CR itself, and this will be verified in future experiments. The works suggested that the Aβ protein‐specific magnetic resonance contrast agent precursor CR‐BSA‐(Gd‐DTPA)n can be used as a potential fluorescence and MR multi‐modal imaging probe precursor to display individual senile plaques in AD. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.     

Deposition of lactoferrin in fibrillar-type senile plaques in the brains of transgenic mouse models of Alzheimer's disease

We and others have previously reported that lactoferrin (LF), which acts as both an iron-binding protein and an inflammatory modulator, is strongly up-regulated in the brains of patients with Alzheimer's disease (AD). We have also studied the expression and localization of LF mRNA in the brain cortices of patients with AD. In this study, we investigated immunohistochemically the localization of LF in the brains of APP-transgenic mice, representing a model of AD. No LF immunoreactivity was detected in the brains of the wild-type mice. In the transgenic AD mice, LF deposition was detected in the brains. Double-immunofluorescence staining with antibodies directed against the amyloid-β peptide (Aβ) and LF localized the LF depositions to amyloid deposits (senile plaques) and regions of amyloid angiopathy. Senile plaque formation precedes LF deposition in AD. In the transgenic mice aged <18 months, most of senile plaques were negative for LF. LF deposits appeared weakly at about 18 months of age in these mice. Both the intensity and number of LF-positive depositions in the transgenic mice increased with age. Double-staining for LF and thioflavin-S revealed that LF accumulated in thioflavin-S-positive, fibrillar-type senile plaques. The up-regulation of LF in the brains of both AD patients and the transgenic mouse model of AD provides evidence of an important role for LF in AD-affected brain tissues.     

Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer's disease mouse model

Although anti-human β-amyloid (Aβ) immunotherapy clears brain β-amyloid plaques in Alzheimer's disease (AD), targeting additional brain plaque constituents to promote clearance has not been attempted. Endogenous murine Aβ is a minor Aβ plaque component in amyloid precursor protein (APP) transgenic AD models, which we show is ∼3%–8% of the total accumulated Aβ in various human APP transgenic mice. Murine Aβ codeposits and colocalizes with human Aβ in amyloid plaques, and the two Aβ species coimmunoprecipitate together from brain extracts. In the human APP transgenic mouse model Tg2576, passive immunization for 8 weeks with a murine-Aβ-specific antibody reduced β-amyloid plaque pathology, robustly decreasing both murine and human Aβ levels. The immunized mice additionally showed improvements in two behavioral assays, odor habituation and nesting behavior. We conclude that passive anti-murine Aβ immunization clears Aβ plaque pathology—including the major human Aβ component—and decreases behavioral deficits, arguing that targeting minor endogenous brain plaque constituents can be beneficial, broadening the range of plaque-associated targets for AD therapeutics.     

Large amounts of neocortical beta A4 deposits without neuritic plaques nor tangles in a psychometrically assessed, non-demented person

An 88-year-old mentally normal woman (Blessed test score = 27) had very large amounts (397/mm2) of deposits stained by anti-beta A4 serum in the first temporal gyrus. Senile plaques and neurofibrillary tangles were lacking on sections stained with the Bodian's silver method, with anti-tau and anti-paired helical filament (anti-PHF) antibodies. The following beta A4 deposits were found in decreasing order of frequency: diffuse (64.8%), stellate (24.4%), primitive (10.2%), classic (0.6%) plaques. Compact plaques were not observed. Diffuse deposits predominated in layers I, III and IV. On the contrary, the rare classic plaques were located in layers II and III. No amyloid angiopathy was seen with Congo red stain although beta A 4 deposits were seen in vessel walls with immunocytochemistry. These data indicate that severe diffuse beta A4 deposits in the neocortex do not induce dementia. They suggest that the development of senile plaques composed of beta A4 amyloid and of degenerating neurites is not related solely to the density of the diffuse beta A4 deposits. Nor does it depend on the regional susceptibility of the nervous tissue since beta A4 deposits were seen in highly vulnerable cortical areas. Some other, as yet unknown, factors seem necessary. In addition, determination of beta A4 level in the neocortex is not sufficient for the diagnosis of dementia of Alzheimer type.     

Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric

Alzheimer's disease (AD) is characterized by deposition of beta-amyloid (Abeta) in diffuse and senile plaques, and variably in vessels. Mutations in the Abeta-encoding region of the amyloid precursor protein (APP) gene are frequently associated with very severe forms of vascular Abeta deposition, sometimes also accompanied by AD pathology. We earlier described a Flemish APP (A692G) mutation causing a form of early-onset AD with a prominent cerebral amyloid angiopathy and unusually large senile plaque cores. The pathogenic basis of Flemish AD is unknown. By image and mass spectrometric Abeta analyses, we demonstrated that in contrast to other familial AD cases with predominant brain Abeta42, Flemish AD patients predominantly deposit Abeta40. On serial histological section analysis we further showed that the neuritic senile plaques in APP692 brains were centered on vessels. Of a total of 2400 senile plaque cores studied from various brain regions from three patients, 68% enclosed a vessel, whereas the remainder were associated with vascular walls. These observations were confirmed by electron microscopy coupled with examination of serial semi-thin plastic sections, as well as three-dimensional observations by confocal microscopy. Diffuse plaques did not associate with vessels, or with neuritic or inflammatory pathology. Together with earlier in vitro data on APP692, our analyses suggest that the altered biological properties of the Flemish APP and Abeta facilitate progressive Abeta deposition in vascular walls that in addition to causing strokes, initiates formation of dense-core senile plaques in the Flemish variant of AD.     

Cerebral amyloid angiopathy

Cerebral amyloid angiopathy is a nonspecific disease entity that has been associated with a number of neuropathologic conditions, the most prominent being dementia and cerebral hemorrhage. It occurs more commonly than is generally appreciated, with implications that may be overlooked. Amyloid deposits are found in the vessels of the leptomeninges and cerebral cortex. There is often a close topographic relation to senile plaques, the histologic abnormality characteristic of Alzheimer's disease and senile dementia. Because of this relation and the well documented presence of amyloid in senile plaques a similar natural history has been postulated for each. Histochemical studies indicate, however, that there are distinct differences between the amyloid deposits in cerebral vessels, and senile plaques. An association between cerebral amyloid angiopathy and other forms of amyloidosis has similarly failed to be established, and a successful form of therapy has yet to be devised.     

The Aβ1–42M35C mutated amyloid peptide Aβ1–42 and the 25–35 fragment fail to mimic the subtype-specificity of actions on recombinant human nicotinic acetylcholine receptors (α7, α4β2, α3β4)

Alzheimer's disease (AD) is a neurodegenerative condition involving accumulation of the β-amyloid peptide, Aβ_1–42. Previously we have shown that amyloid peptides (Aβ_1–42, Aβ_1–40) have different actions on the three major brain nicotinic acetylcholine receptor (nAChR) subtypes (α7, α4β2 and α3β4). The methionine in position 35 of Aβ (M35) has been shown to be important in the toxicity of Aβ and the 25–35 fragment can mimic some of the actions of the Aβ_1–42 peptide. However, the extent to which this mutant and the fragment mimic subtype selectivity is unknown. Two-electrode voltage-clamp electrophysiology has been used to study the actions on α7, α4β2 and α3β4 recombinant nAChRs expressed in Xenopus laevis oocytes of full length Aβ_1–42, and Aβ peptide fragments, scrambled peptides, and the Aβ_1–42 peptide containing mutations of the methionine in position 35. The Aβ_25–35 fragment did not display subunit specificity. Aβ_1–42 with an M35C mutation showed similar subtype-specificity to wild-type Aβ_1–42. However, Aβ_1–42 with an M35V substitution reduced the peak amplitude of ACh-induced currents recorded from α4β2 nAChRs, but did not affect those recorded from α7 or α3β4. These results indicate that the amino acid in position 35 of Aβ_1–42 is an important determinant of the subtype-specificity of this peptide on human recombinant α7, α4β2 and α3β4 nAChRs and that the 25–35 fragment fails to mimic all of the actions of the full-length peptide.     

High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain

Cortical amyloid-beta (Abeta) deposition is considered essential in Alzheimer's disease (AD) and is also detectable in nondemented individuals with pathologic aging (PA). The present work presents a detailed analysis of the Abeta composition in various plaque types from human AD and PA cases, compared with plaque Abeta isolated from PS2APP mice. To determine minute amounts of Abeta from 30 to 50 laser-dissected amyloid deposits, we used a highly sensitive mass spectrometry procedure after restriction protease lysyl endopeptidase (Lys-C) digestion. This approach allowed the analysis of the amino-terminus and, including a novel ionization modifier, for the first time the carboxy-terminus of Abeta at a detection limit of approximately 200 fmol. In addition, full length Abeta 40/42 and pyroglutamate 3-42 were analyzed using a highly sensitive urea-based Western blot procedure. Generally, Abeta fragments were less accessible in human deposits, indicative of more posttranslational modifications. Thioflavine S positive cored plaques in AD were found to contain predominantly Abeta 42, whereas thioflavine S positive compact plaques and vascular amyloid consist mostly of Abeta 40. Diffuse plaques from AD and PA, as well as from PS2APP mice are composed predominantly of Abeta 1-42. Despite biochemical similarities in human and PS2APP mice, immuno-electron microscopy revealed an extensive extracellular matrix associated with Abeta fibrils in AD, specifically in diffuse plaques. Amino-terminal truncations of Abeta, especially pyroglutamate 3-40/42, are more frequently found in human plaques. In cored plaques we measured an increase of N-terminal truncations of approximately 20% between Braak stages IV to VI. In contrast, diffuse plaques of AD and PA cases, show consistently only low levels of amino-terminal truncations. Our data support the concept that diffuse plaques represent initial Abeta deposits but indicate a structural difference for Abeta depositions in human AD compared with PS2APP mice already at the stage of diffuse plaque formation.