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N-truncated Aβ4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aβ peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aβ4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aβ4-42 is as toxic as pyroglutamate Aβ3-42 and Aβ1-42. In line with these findings, treatment of wildtype mice using intraventricular Aβ injection induced significant working memory deficits with Aβ4-42, pyroglutamate Aβ3-42 and Aβ1-42. Transgenic mice expressing Aβ4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aβ4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aβ4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.

Alzheimer's disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human beta-amyloid (Abeta) precursor protein. Abeta(x-42) is the major form of Abeta species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Abeta and thioflavine-S-positive intracellular material but not with extracellular Abeta deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APP(SL)PS1KI mice further confirm the critical role of intraneuronal Abeta(42) in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.

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Accumulating evidence points to an important role of intraneuronal Ab as a trigger of the pathological cascade of events leading to neurodegeneration and eventually to Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and change in personality. In the present article, we review recent findings on intracellular monomeric and oligomeric b-amyloid (Ab) generation and its pathological function in cell culture, transgenic AD mouse models and post mortem brain tissue of AD and Down syndrome patients, as well as its interaction with oxidative stress and its relevance in apoptotic cell death. Based on these results, a modified Ab hypothesis is formulated, that integrates biochemical, neuropathological and genetic observations with AD-typical neuron loss and plaque formation.

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Pyroglutamate-modified amyloid-␤ (A␤ pE3 ) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of A␤ pE3-42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of A␤ pE3 . In this minireview, we summarize the current knowledge on A␤ pE3 , discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker.When Alois Alzheimer presented the case of his patient Auguste Deter at the Tübingen meeting of the Southwest German Psychiatrists in 1906, he did not attract much attention or stimulate any discussion in the audience. The young doctor likely would not have believed that, 100 years later, the disease that now holds his name would be the most common cause of dementia and a source of a critical medical and economical problem. At this meeting, Alzheimer presented Auguste Deter's symptoms and reported the histopathological features that are now associated with Alzheimer disease (AD) 2 : neuron loss, extracellular amyloid plaques, and intracellular neurofibrillary tangles. For more than 2 decades, the amyloid hypothesis has been the cardinal hypothesis in describing the sequence of AD etiology. The amyloid hypothesis considers amyloid-␤ (A␤) deposition to be the causative event of AD pathology and that neurofibrillary tangles, cell loss, vascular damage, and dementia occur as a consequence of it (1). However, it has been recently suggested that the extracellular formation of A␤ plaques and other AD pathological events are preceded by intraneuronal A␤ accumulation, giving rise to a modified amyloid hypothesis (2).The story of successful discoveries in modern AD research using novel molecular biological tools started with the biochemical analysis of ␤-amyloid-containing blood vessels (congophilic amyloid angiopathy) (3) and amyloid plaques consisting of A␤ (4), which led to the isolation and sequencing of the gene encoding the larger amyloid precursor protein (APP) (5, 6).In vitro and in vivo analyses of amyloid deposits in AD revealed various N-and C-terminal variants (4, 7, 8). Increased C-terminal length of A␤ (from A␤ x-40 to A␤ x-42 ) in AD enhanced aggregation and early deposition and promoted the toxicity of A␤ (9 -11). Recently, A␤ 1-43 has been discussed as a novel toxic peptide in AD (12).Beside A␤ peptides, starting with aspartate as the first amino acid (A␤ 1-x ), several N-terminally truncated and modified A␤ species have been described (4, 13-15). Among A␤ species present in AD plaques, Lewis et al. (16) reported that A␤ 4 -42 is a relatively abundant species in AD, aged control, and vascular dementia patients. Using immunoprecipitation in combination with mass spectrome...

According to the "amyloid hypothesis of Alzheimer's disease," beta-amyloid is the primary driving force in Alzheimer's disease pathogenesis. Despite the development of many transgenic mouse lines developing abundant beta-amyloid-containing plaques in the brain, the actual link between amyloid plaques and neuron loss has not been clearly established, as reports on neuron loss in these models have remained controversial. We investigated transgenic mice expressing human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and human mutant presenilin-1 (PS-1 M146L). Stereologic and image analyses revealed substantial age-related neuron loss in the hippocampal pyramidal cell layer of APP/PS-1 double-transgenic mice. The loss of neurons was observed at sites of Abeta aggregation and surrounding astrocytes but, most importantly, was also clearly observed in areas of the parenchyma distant from plaques. These findings point to the potential involvement of more than one mechanism in hippocampal neuron loss in this APP/PS-1 double-transgenic mouse model of Alzheimer's disease.