An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities

Abstract

We previously developed single App knock-in mouse models of Alzheimer’s disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation ( App NL-G-F and App NL-F mice). We have now generated App knock-in mice devoid of the Swedish mutations ( App G-F mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by App G-F mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated Aβ production in App G-F mice, but not in App NL-G-F mice, indicating that the App G-F mice are more suitable for preclinical studies of β-secretase inhibition given that most patients with AD do not carry the Swedish mutations. Comparison of isogenic App knock-in lines revealed that multiple factors, including elevated C-terminal fragment β (CTF-β) and humanization of Aβ might influence endosomal alterations in vivo. Thus, experimental comparisons between different isogenic App , knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD.

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication

“…In addition, MS1262 has greater potency than any existing G9a inhibitors (e.g., BIX-01294, UNC0638, UNC0642). We studied the MS1262 effects on two AD mouse models, the 5XFAD and the APP NLGF knock-in (KI) 26 mice, which are clinically relevant mouse models of AD that comprehensively recapitulate major pathological features of AD patients.…”

“…In addition, MS1262 has greater potency than any existing G9a inhibitors (e.g., BIX-01294, UNC0638, UNC0642). We studied the MS1262 effects on two AD mouse models, the 5XFAD and the APP NLGF knock-in (KI) 26 mice, which are clinically relevant mouse models of AD that comprehensively recapitulate major pathological features of AD patients. Consistently, we found that intermittent MS1262 treatment of both types of AD mice not only fully restored cognitive functions to healthy levels but also reduced anxiety- and depressive-like behavior, typical noncognitive (affective) symptoms of AD patients.…”

Plaque-associated endogenous IgG and its impact on immunohistochemical detection of mouse monoclonal IgG antibodies in mouse models of Alzheimer’s disease

“…We first assessed endogenous IgG accumulation in the brain parenchyma of an App-KI mouse line, App NL-G-F mouse model 30 . App NL-G-F line, which expresses humanized Aβ peptide and harbors the Swedish (KM670/671NL), Beyreuther/Iberian (I716F), and Arctic (E693G) mutations, manifests Aβ plaque deposition and cognitive impairments earlier than other App-KI mouse lines [30][31][32] . We used the mouse model aged 6 to 7 months to examine the accumulation of endogenous IgG in its brain parenchyma when memory impairment is observed 30 .…”

Updates on mouse models of Alzheimer’s disease

“…At 8 months of age, Aβ plaques were detected in multiple brain regions with highest burden in cortical and hippocampal regions [ 99 ]. Initial Aβ deposition was observed as early as 4 months of age in APP GF mice and at 12 months of age, Aβ deposition in APP GF mice was detected to be in a much larger brain area than that in APP NL−F mice but in a lesser area than that in APP NLGF mice [ 100 ]. It was also found that p-tau 217, p-tau 231, and a fraction of p-tau 181 were detected around Aβ plaques only in APP NLGF mice but not in APP NL or wildtype mice, suggesting that these tau pathologies may be induced by Aβ plaque burden [ 101 ].…”

“…Despite an early and aggressive Aβ amyloidosis in APP NLGF , neuroinflammatory responses were not intense at 6–9 months of age, but greater reactive gliosis was observed in cortical and hippocampal regions by 15–18 months of age [ 98 ]. On the other hand, amyloidosis in APP GF mice were accompanied with neuroinflammation, as shown by reactive astrocytes and activated microglia at 22 months of age [ 100 ].…”