Comparative Analysis of Amyloid-β Chemical Structure and Amyloid Plaque Morphology of Transgenic Mouse and Alzheimer's Disease Brains

Abstract

We have undertaken an integrated chemical and morphological comparison of the amyloid-␤ (A␤) molecules and the amyloid plaques present in the brains of APP23 transgenic (tg) mice and human Alzheimer's disease (AD) patients. Despite an apparent overall structural resemblance to AD pathology, our detailed chemical analyses revealed that although the amyloid plaques characteristic of AD contain cores that are highly resistant to chemical and physical disruption, the tg mice produced amyloid cores that were completely soluble in buffers containing SDS. A␤ chemical alterations account for the extreme stability of AD plaque core amyloid. The corresponding lack of post-translational modifications such as N-terminal degradation, isomerization, racemization, pyroglutamyl formation, oxidation, and covalently linked dimers in tg mouse A␤ provides an explanation for the differences in solubility between human AD and the APP23 tg mouse plaques. We hypothesize either that insufficient time is available for A␤ structural modifications or that the complex species-specific environment of the human disease is not precisely replicated in the tg mice. The appraisal of therapeutic agents or protocols in these animal models must be judged in the context of the lack of complete equivalence between the transgenic mouse plaques and the human AD lesions. Alzheimer's disease (AD)1 is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques composed principally of amyloid-␤ (A␤) surrounded by dystrophic neurites (1). This association and the realization that the basis of certain early-onset familial forms of AD seems to be the enhanced production of one or more A␤ peptides have led to the hypothesis that A␤ is intimately involved in the AD pathogenic process (2). A promising experimental approach to unraveling the role(s) of A␤ in AD pathology has been the construction and characterization of transgenic mice that overexpress the amyloid precursor protein (APP) (3-12). Several transgenic mouse lines have been described that produce A␤ deposits that accumulate in an agedependent fashion and morphologically resemble the senile plaques characteristic of human AD (3,6,8,12,37,38).The APP23 transgenic (tg) mice contain an APP751 cDNA with the Swedish familial AD mutation under the control of the neuron-specific Thy-1 promoter and express this human gene at levels 7-fold greater than endogenous murine APP (12). Longitudinal studies of these mice have revealed that extracellular amyloid deposits become evident as the APP23 tg mice age. These deposits exhibit, at their earliest appearance, the Congo red birefringence characteristic of the dense core plaques of human AD (12). A gradual progression from a diffuse deposit to a dense plaque is not a feature of the APP23 tg mouse pathology, paralleling our previous finding (13) that the diffuse amyloid deposits of AD do not represent a precursor developmental stage of senile plaques.A transgenic mouse model system that faithfully mimics every aspect of AD h...

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

“…In Tg2576 mice, truncated and modified A␤ isoforms do not appear before 1 year of age and comprise ϳ5% of total A␤ (35). A␤ pE3 and other modified forms of A␤ were reported to be absent in APP23 mice until almost 2 years of age (36) or low in PS2APP mice (15). Using another approach, Maeda and colleagues (37) demonstrated that the localization and abundance of [ 11 C]PIB autoradiographic signals were associated closely with A␤ pE3 plaques in AD and different APP transgenic mouse brains.…”

“…A␤ pE3 isoforms have been identified by several groups in AD brains (12,13,15,36,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52). N-terminal deletions generally enhance aggregation of ␤-amyloid peptides in vitro (53).…”

Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

“…10 A-D). Two major types of plaques, dense and diffuse plaques, were present in our model as in others (18,19) (SI Fig. 10 F and G), and those plaques were quantified independently.…”

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

“…A␤ pE3 and other modified forms of A␤ are absent in another mouse model, APP23, until 22 months of age. The difference in the composition of A␤ pools between AD and the APP23 mouse model might account for the different plaque morphology and the high solubility of A␤ peptides in APP23 mice (54). The discrepancy in the A␤ isoforms between AD and mouse models might be due to the short life span of the mice compared with the decades available for A␤ post-translational modification in AD.…”