DNA polymerase β decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease

Abstract

SummaryAlzheimer's disease (AD) involves the progressive degeneration of neurons critical for learning and memory. In addition, patients with AD typically exhibit impaired olfaction associated with neuronal degeneration in the olfactory bulb (OB). Because DNA base excision repair (BER) is reduced in brain cells during normal aging and AD, we determined whether inefficient BER due to reduced DNA polymerase‐β (Polβ) levels renders OB neurons vulnerable to degeneration in the 3xTgAD mouse model of AD. We interrogated OB histopathology and olfactory function in wild‐type and 3xTgAD mice with normal or reduced Polβ levels. Compared to wild‐type control mice, Polβ heterozygous (Polβ+/−), and 3xTgAD mice, 3xTgAD/Polβ+/− mice exhibited impaired performance in a buried food test of olfaction. Polβ deficiency did not affect the proliferation of OB neural progenitor cells in the subventricular zone. However, numbers of newly generated neurons were reduced by approximately 25% in Polβ+/− and 3xTgAD mice, and by over 60% in the 3xTgAD/Polβ+/− mice compared to wild‐type control mice. Analyses of DNA damage and apoptosis revealed significantly greater degeneration of OB neurons in 3xTgAD/Polβ+/− mice compared to 3xTgAD mice. Levels of amyloid β‐peptide (Aβ) accumulation in the OB were similar in 3xTgAD and 3xTgAD/Polβ+/− mice, and cultured Polβ‐deficient neurons exhibited increased vulnerability to Aβ‐induced death. Olfactory deficit is an early sign in human AD, but the mechanism is not yet understood. Our findings in a new AD mouse model demonstrate that diminution of BER can endanger OB neurons, and suggest a mechanism underlying early olfactory impairment in AD.

NAD + supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency

“…To assess the potential impact of DNA damage and repair in the etiology of AD, we crossed a null allele for Polβ into the 3xTgAD mouse to generate the 3xTgAD/Polβ +/− mice. Our earlier studies demonstrate that the 3xTgAD/Polβ +/− mouse accumulates more DNA damage and exhibits neuronal death in brain regions and that it has a defect in olfactory function that resembles the defective olfaction observed in AD patients (35,36). Thus, the 3xTgAD/ Polβ +/− mice appear to recapitulate features of AD in humans better than previously available mouse models of AD (35).…”

Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy

“…Polβ deficiency exacerbates AD phenotypes and mitochondrial dysfunction [34,58,77], and post-mortem brain extracts from AD patients showed impaired Polβ activity [88]. Polβ is the central nuclear BER DNA polymerase in mammalian cells.…”

“…Recent reports have shown the presence of the major nuclear BER DNA polymerase, DNA polymerase β (Polβ), in mitochondria in the brain [65,76], with a likely role in mtDNA repair. 3xTgAD mice with a 50% reduction of Polβ (3xTg AD/Polβ +/− ), which also contain a mutated version of human tau, display exacerbated AD phenotypes with impaired cellular bioenergetics and mitochondrial dysfunction [58,77].…”

DNA polymerase β: A missing link of the base excision repair machinery in mammalian mitochondria

“…Also, a cross-linked protein consistent with pol β was observed in Percoll gradient purified mitochondria, but was considered a contaminant [65]. Fourth, Bohr and his associates recently found mitochondrial metabolism deficiency phenotypes in a mouse model with reduced expression of pol β due to haploinsufficiency of the pol β gene [74,75]. Interestingly, after the current manuscript was prepared Bohr and his associates confirmed the absence of pol β in mitochondria isolated from mouse liver and also detected pol β in mitochondria from brain tissue as well as from cultured mammalian cells [76].…”