Pyroglutamate-modified amyloid-β protein demonstrates similar properties in an Alzheimer's disease familial mutant knock-in mouse and Alzheimer's disease brain.

N-terminally truncated, pyroglutamate-modified amyloid-β (Aβ) peptides are major constituents of amyloid deposits in Alzheimer's disease (AD). Using a newly developed ELISA for Aβ modified at glutamate 3 with a pyroglutamate (pE3Aβ), brain pE3Aβ was characterized in human AD in an AD mouse model harboring double knock-in amyloid precursor protein (APP)-KM670/671NL and presenilin 1 (PS1)-P264L (APP/PS1-dKI) mutations, and in a second mouse model with transgenic overexpression of human APP695 with APP-KM670/671NL (Tg2576). pE3Aβ increased in the AD brain versus age-matched controls, with pE3Aβ/total Aβ at 45 and 10%, respectively. Compared to controls, the AD brain demonstrated 8.5-fold increased pE3Aβ compared to non-pE3Aβ species, which increased 2.7-fold. In the APP/PS1-dKI brain, pE3Aβ/total Aβ increased from 7% at 3 months to 16 and 19% at 15 and 19 months, respectively. In Tg2576, pE3Aβ/total Aβ was only 1.5% at 19 months, suggesting that APP/PS1-dKI, despite less total Aβ compared to Tg2576 at comparable ages, more closely mimics AD brain pathology. This report supports a significant role for pE3Aβ in AD pathogenesis by confirming that pE3Aβ represents a large fraction of Aβ within the AD brain. Compared to the age-matched control brain, pE3Aβ increased to a greater extent compared to Aβ species without this N-terminal modification. Further, the APP/PS1-dKI model more closely resembles the AD brain in this regard, compared to the Tg2576 model.

Wu G ，Miller RA ，Connolly B ，Marcus J ，Renger J ，Savage MJ ... -  《-》

Deposition of mouse amyloid beta in human APP/PS1 double and single AD model transgenic mice.

van Groen T ，Kiliaan AJ ，Kadish I 《NEUROBIOLOGY OF DISEASE》

The effect of focal brain injury on beta-amyloid plaque deposition, inflammation and synapses in the APP/PS1 mouse model of Alzheimer's disease.

Traumatic brain injury is a risk factor for Alzheimer's disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Aβ) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Aβ plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APPSWE, PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aβ antibody) MOAB-2-labeled plaques at either 24h or 7d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Aβ plaques but focal injury had no statistically significant (p>0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24h PI or 7d PI. There was a significant (p<0.001) increase in cross-sectional cortical area occupied by Iba-1 positive microglia in injured mice compared to sham animals, however this response did not differ between APP/PS1 and Wt mice (p>0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24h PI (compared to sites distant to the injury and the corresponding area in sham mice; p<0.01), but not after 7d PI (p>0.05). There was no significant effect of genotype on this response (p>0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Aβ plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Aβ plaque pathology that causes synaptic degeneration.

Collins JM ，King AE ，Woodhouse A ，Kirkcaldie MT ，Vickers JC ... -  《-》

Effects of accelerated senescence on learning and memory, locomotion and anxiety-like behavior in APP/PS1 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a deficit in motor and spatial learning-memory and alteration of non-cognitive behavior. The generation of transgenic mice with presence of AD pathologies that cause learning and memory deficits has led to improved understanding of the behavioral and pathophysiological processes underlying AD. A novel APP/PS1 mouse model in the senescence accelerated mouse prone 8 (SAMP8) background--SAMP8 APP/PS1 was generated. To assess the behavioral and other AD-related changes in this SAMP8 APP/PS1 model, the present report covers a phenotypical analysis of this model for working memory, spatial memory, motor performance and anxiety-like behavior. SAMP8 APP/PS1 mice showed motor and spatial memory impairments, together with an increase of locomotor activity and lower anxiety-like behavior at 9months old. In contrast, C57 APP/PS1 and SAMP8 wild type mice were inconspicuous in all of these tasks and properties except C57 APP/PS1 mice which showed motor memory impairment in the shuttle box task at 9 months old. Standard senescence-associated beta-galactosidase (SA-beta-GAL) staining and amyloid beta (Aβ) immunohistochemistry showed more severe pathological changes in the SAMP8 APP/PS1 mice. SAMP8 APP/PS1 mice exhibited earlier deficits in their non-cognitive and cognitive behaviors which are coincident in the AD patient and the results suggest that this new type of mice might be a better model for studying the age-related dementia of the Alzheimer type and for assessing the potential therapeutic agents for AD.

Lok K ，Zhao H ，Zhang C ，He N ，Shen H ，Wang Z ，Zhao W ，Yin M ... -  《-》

ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology.

In Alzheimer's disease (AD), the accumulation and deposition of amyloid-β (Aβ) peptides in the brain is a central event. Aβ is cleaved from amyloid precursor protein (APP) by β-secretase and γ-secretase mainly in neurons. Although mutations inAPP,PS1, orPS2cause early-onset familial AD,ABCA7encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which itsloss-of-functionvariants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7(-/-)) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit.In vivomicrodialysis studies indicated that the clearance rate of Aβ was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to Aβ by increasing the levels of β-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2α (eIF2α). In the brains of APP/PS1;Abca7(-/-)mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis. Gene variants inABCA7encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-β (Aβ) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain Aβ deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Aβ production by increasing the levels of β-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Aβ clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.

Sakae N ，Liu CC ，Shinohara M ，Frisch-Daiello J ，Ma L ，Yamazaki Y ，Tachibana M ，Younkin L ，Kurti A ，Carrasquillo MM ，Zou F ，Sevlever D ，Bisceglio G ，Gan M ，Fol R ，Knight P ，Wang M ，Han X ，Fryer JD ，Fitzgerald ML ，Ohyagi Y ，Younkin SG ，Bu G ，Kanekiyo T ... -  《-》