Abstract
The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer’s disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.
Highlights
Cerebral accumulation of amyloid β (Aβ) oligomers is believed to be the initial step in the pathogenesis of Alzheimer’s disease (AD) [2, 29]
Data in Generation of OSK-KI mice OSK-KI mice were generated by homologous recombination with a targeting vector containing mouse amyloid precursor protein (APP) fragment around exon 17 in which codon 693 was deleted (Fig. 1a)
Compared with non-KI littermates, homozygotes but not heterozygotes showed a significant decrease in NeuN-positive cells in both regions at 24 months (Fig. 4f). These results indicate that the Osaka mutation causes Aβ-related neuropathology in a recessive hereditary manner
Summary
Cerebral accumulation of Aβ oligomers is believed to be the initial step in the pathogenesis of Alzheimer’s disease (AD) [2, 29]. Aβ is generated from amyloid precursor protein (APP) by the function of two distinct enzymes, β- and γ-secretase [14]. Genetic studies have found that mutations in APP (chromosome 21), PSEN1 (chromosome 14), and PSEN2 (chromosome 1) are linked to familial AD [3]. The inheritance of pathogenic mutations can be defined into two types, dominant and recessive, according to the impact of the mutant allele on the phenotype [22]. Dominant mutations cause disease even in heterozygotes by 1) gain-of-toxic-function of the gene product, 2) loss-of-function with dominant-negative effect, and 3) loss-of-function if 50% level of the normal gene product is not sufficient for normal gene function (haploinsufficiency). Recessive mutations cause disease only in homozygotes primarily by loss-offunction: heterozygotes do not show pathogenic phenotypes, since the wild-type counterpart overcomes the deficiency of the mutant protein
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