Longitudinal, Quantitative Assessment of Amyloid, Neuroinflammation, and Anti-Amyloid Treatment in a Living Mouse Model of Alzheimer's Disease Enabled by Positron Emission Tomography

Tian

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

192

168

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.Alzheimer's | amyloid | imaging | fluorescence | curcumin

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 68%

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

Tian

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

192

168

“…We also detected the presence of N3pE-Aβ in APP Tg x PS1-R278I knockin mouse brains, a finding that is supported by a report quantitatively describing N3pE-Aβ42 and N3pE-Aβ43 in the brains of FAD and SAD patients 2 . It is of particular interest that Pittsburgh Compound B, a probe for amyloid imaging by positron emission tomography, selectively binds to N3pE-Aβ 26 , implying that N3pE-Aβ42/43 could be particularly prone to seed deposition of other Aβ species, consistent with previous reports 28 . It is also possible that the mutation might affect the interaction of PS1 with other substrates or alter its property of non-γ-secretase activity 29 .…”

Section: Months Of Age (Data Not Shown) These Observations Point To supporting

confidence: 87%

“…6f-h). Interestingly, Aβ species with the 3rd N-terminal residue converted to pyroglutamate (N3pE-Aβ), a potently pathogenic Aβ subspecies [26][27][28][29] , also colocalized with plaque cores and deposited more abundantly in APP Tg x PS1-R278I mice than in APP Tg x PS1-M146V animals ( Supplementary Fig. 14).…”

Section: App Tg X Ps1-r278i Versus App Tg X Ps1-m146v Knockin Micementioning

confidence: 99%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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...

Journal of Biological Chemistry

“…A␤ pE3 and other modified forms of A␤ were reported to be absent in APP23 mice until almost 2 years of age (36) or low in PS2APP mice (15). Using another approach, Maeda and colleagues (37) demonstrated that the localization and abundance of [ 11 C]PIB autoradiographic signals were associated closely with A␤ pE3 plaques in AD and different APP transgenic mouse brains. This observation suggests that the [ 11 C]PIB-PET retention signal depends on the accumulation of specific A␤ subtypes (37).…”

Section: Discussionmentioning

confidence: 99%

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Wittnam

Portelius

Zetterberg

et al. 2012