[Abstract unavailable

Experimental studies of Alzheimer's disease have largely depended on transgenic mice overexpressing amyloid precursor protein (APP). These mice, however, suffer from artificial phenotypes because, in addition to amyloid β peptide (Aβ), they overproduce other APP fragments. We generated knock-in mice that harbor Swedish and Beyreuther/Iberian mutations with and without the Arctic mutation in the APP gene. The mice showed typical Aβ pathology, neuroinflammation and memory impairment in an age-dependent manner.

No abstract

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.

Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

Alzheimer's disease (AD) is a neurodegenerative disease biochemically characterized by aberrant protein aggregation, including amyloid beta (Aβ) peptide accumulation. Protein aggregates in the cell are cleared by autophagy, a mechanism impaired in AD. To investigate the role of autophagy in Aβ pathology in vivo, we crossed amyloid precursor protein (APP) transgenic mice with mice lacking autophagy in excitatory forebrain neurons obtained by conditional knockout of autophagy-related protein 7. Remarkably, autophagy deficiency drastically reduced extracellular Aβ plaque burden. This reduction of Aβ plaque load was due to inhibition of Aβ secretion, which led to aberrant intraneuronal Aβ accumulation in the perinuclear region. Moreover, autophagy-deficiency-induced neurodegeneration was exacerbated by amyloidosis, which together severely impaired memory. Our results establish a function for autophagy in Aβ metabolism: autophagy influences secretion of Aβ to the extracellular space and thereby directly affects Aβ plaque formation, a pathological hallmark of AD.

Partial migration, whereby only a fraction of the population migrates, is thought to be the most common type of migration in the animal kingdom, and can have important ecological and evolutionary consequences. Despite this, the factors that influence which individuals migrate and which remain resident are poorly understood. Recent work has shown that consistent individual differences in personality traits in animals can be ecologically important, but field studies integrating personality traits with migratory behaviour are extremely rare. In this study, we investigate the influence of individual boldness, an important personality trait, upon the migratory propensity of roach, a freshwater fish, over two consecutive migration seasons. We assay and individually tag 460 roach and show that boldness influences migratory propensity, with bold individuals being more likely to migrate than shy fish. Our data suggest that an extremely widespread personality trait in animals can have significant ecological consequences via influencing individual-level migratory behaviour.

We previously showed that mRNA 3 0 end cleavage reaction in cell extracts is strongly but transiently inhibited under DNA-damaging conditions. The cleavage stimulation factor-50 (CstF-50) has a role in this response, providing a link between transcription-coupled RNA processing and DNA repair. In this study, we show that CstF-50 interacts with nuclear poly(A)-specific ribonuclease (PARN) using in vitro and in extracts of UV-exposed cells. The CstF-50/ PARN complex formation has a role in the inhibition of 3 0 cleavage and activation of deadenylation upon DNA damage. Extending these results, we found that the tumour suppressor BARD1, which is involved in the UV-induced inhibition of 3 0 cleavage, strongly activates deadenylation by PARN in the presence of CstF-50, and that CstF-50/ BARD1 can revert the cap-binding protein-80 (CBP80)-mediated inhibition of PARN activity. We also provide evidence that PARN along with the CstF/BARD1 complex participates in the regulation of endogenous transcripts under DNA-damaging conditions. We speculate that the interplay between polyadenylation, deadenylation and tumour-suppressor factors might prevent the expression of prematurely terminated messengers, contributing to control of gene expression under different cellular conditions.