Increased neuronal PreP activity reduces Aβ accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model

Abstract

Accumulation of amyloid-β (Aβ) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Aβ and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Aβ degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates Aβ-mediated reduction of long-term potentiation (LTP). Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial Aβ along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD.

Increased Electron Paramagnetic Resonance Signal Correlates with Mitochondrial Dysfunction and Oxidative Stress in an Alzheimer’s disease Mouse Brain

“…Moreover, Aβ can induce oxidative stress and increase production of ROS, both of which impair mitochondrial function. In turn, oxidative stress also promotes Aβ deposition [2, 4, 5, 40], forming a vicious cycle of promoting neurodegeneration. Given the key role of ROS in early onset and progression of AD, developing a highly sensitive and specific probe/method to detect oxidative stress would be critical for studying the initiation of AD and monitoring AD progression.…”

“…Given that mitochondria are the major resource of ROS generation and that mitochondrial dysfunction occurs in Aβ-rich mAPP brain, damaged mitochondria from mAPP brain could be a major resource of ROS relevant to amyloid pathology. Indeed, mitochondria-derived superoxide was significantly elevated in mAPP hippocampal and cortical neurons, indicating increased ROS accumulation in Aβ-loaded mitochondria [2, 5]. We have successfully detected increased levels of ROS in Aβ-enriched mAPP brain compared with those from nonTg brain at the age of 8–9 months.…”

“…AD is pathologically defined by aggregation of amyloid-β (Aβ) peptide that has been derived from pathologically processed amyloid-β protein precursor (AβPP) in extracellular senile plagues and neurofibrillary tangles which consist of hyperphosphorylated tau protein and lead to severe neuronal loss through oxidative stress and neurodegeneration [2, 3]. The mitochondrial dysfunction and increased oxidative stress have been observed in AD-affected brain and mouse model for AD [2, 4, 5].…”

“…AD is pathologically defined by aggregation of amyloid-β (Aβ) peptide that has been derived from pathologically processed amyloid-β protein precursor (AβPP) in extracellular senile plagues and neurofibrillary tangles which consist of hyperphosphorylated tau protein and lead to severe neuronal loss through oxidative stress and neurodegeneration [2, 3]. The mitochondrial dysfunction and increased oxidative stress have been observed in AD-affected brain and mouse model for AD [2, 4, 5]. Oxidative stress leads to an alteration in redox state resulting from an imbalance between the generation and detoxification of reactive oxygen species (ROS), which can be detected in the blood, cerebrospinal fluid, and brain of AD patients [6–9].…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…Intra-cerebroventricular injections of beta-amyloid resulted in age-related increase in cholinergic loss and microglial activation (Nell et al, 2015). Increased neuronal expression of presequence protease (PreP) decreased the accumulation of beta-amyloid in synaptic mitochondria and the neuroinflammatory response (Fang et al, 2015), showing a link between the accumulation of insoluble proteins and neuroinflammation. In addition, having the apolipoprotein E4 (APOE) allele, the strongest genetic risk factor for the development of Alzheimer's disease, increases microglial reactivity in the amyloid plaques of a mouse model of beta-amyloid deposition, suggesting a role for APOE in modulation beta-amyloid-induced neuroinflammation in Alzheimer's disease progression (Rodriguez et al, 2014).…”