Molecular imaging of Alzheimer’s disease–related gamma-secretase in mice and nonhuman primates

Abstract

The pathogenesis of Alzheimer’s disease (AD) is primarily driven by brain accumulation of the amyloid-β-42 (Aβ42) peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. γ-Secretase is a prime drug target for AD; however, its brain regional expression and distribution remain largely unknown. Here, we are aimed at developing molecular imaging tools for visualizing γ-secretase. We used our recently developed γ-secretase modulators (GSMs) and synthesized our GSM-based imaging agent, [11C]SGSM-15606. We subsequently performed molecular imaging in rodents, including AD transgenic animals, and macaques, which revealed that our probe displayed good brain uptake and selectivity, stable metabolism, and appropriate kinetics and distribution for imaging γ-secretase in the brain. Interestingly, rodents and macaques shared certain brain areas with high γ-secretase expression, suggesting a functional conservation of γ-secretase. Collectively, we have provided the first molecular brain imaging of γ-secretase, which may not only accelerate our drug discovery for AD but also advance our understanding of AD.

γ-PGA-Rich Chungkookjang, Short-Term Fermented Soybeans: Prevents Memory Impairment by Modulating Brain Insulin Sensitivity, Neuro-Inflammation, and the Gut–Microbiome–Brain Axis

“…Brain insulin resistance decreases glucose utilization of the brain, and it is linked to the low cerebral metabolic rate of glucose that occurs in people with cognitive decline and dementia [ 60 , 61 ]. Furthermore, systemic and brain glucose metabolism has demonstrated a linearly positive relationship in the healthy elderly [ 62 ]. Type 2 diabetes accelerates neurodegeneration by stimulating tau phosphorylation to increase amyloid-β deposition in the hippocampus of Alzheimer’s disease patients [ 56 ].…”

“…In addition to brain insulin resistance, mitochondrial dysfunction and neuroinflammation elevate reactive oxygen species that activate β-secretase and γ-secretase. These enzymes produce amyloid-β from amyloid precursor proteins in mice and nonhuman primates [ 62 ]. Figure 2 suggests the possible mechanism of chungkookjang in glucose and memory function.…”

CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

“…The selective survival of plaque-associated microglia can be functionally relevant, as these cells may play an important role in plaque compaction and limiting toxicity [ 8 , 68 , 70 , 73 ]. To further understand how PLX3397 treatment affects microglia under conditions of ATN pathology, we performed scRNA-Seq analysis on CD45 + immune cells isolated from brains of tau-seeded F + /T + that were or were not treated with PLX chow for 1.5 months (Fig.…”

“…This reveals the detrimental contribution of microglia to disease pathology during ATN progression and is in line with previous work that has reported their detrimental role in tau models of AD [ 2 , 16 , 25 , 31 , 35 , 38 , 39 , 56 , 72 ]. However, it is possible that plaque-associated DAMs compact amyloid plaques and limit amyloid toxicity [ 8 , 68 , 70 , 73 ]. While this needs to be further examined under conditions of ATN progression, their incomplete depletion may thus be an asset for therapeutic targeting.…”

“…At later disease stages, when mature amyloid plaques are abundant, microglial depletion no longer affects plaque load [ 55 ]. However, microglia remain important for compacting plaques and limiting their toxicity [ 8 , 68 , 70 , 73 ], a process in which TREM2 has been shown to play a key role [ 68 , 70 , 73 ]. As it is emerging that microglia may limit amyloid toxicity and formation of plaque-associated dystrophic neurites, but also exacerbate tauopathy, a remaining question is how these cells shape overall disease pathology in combined models that recapitulate the human ATN spectrum.…”