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

ABSTRACT: Alzheimer'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-? (Pol?) 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 Pol? levels. Compared to wild-type control mice, Pol? heterozygous (Pol?^+/- ), and 3xTgAD mice, 3xTgAD/Pol?^+/- mice exhibited impaired performance in a buried food test of olfaction. Pol? 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 Pol?^+/- and 3xTgAD mice, and by over 60% in the 3xTgAD/Pol?^+/- mice compared to wild-type control mice. Analyses of DNA damage and apoptosis revealed significantly greater degeneration of OB neurons in 3xTgAD/Pol?^+/- mice compared to 3xTgAD mice. Levels of amyloid ?-peptide (A?) accumulation in the OB were similar in 3xTgAD and 3xTgAD/Pol?^+/- mice, and cultured Pol?-deficient neurons exhibited increased vulnerability to A?-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.

SUBMITTER: Misiak M

PROVIDER: S-EPMC5242308 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Misiak Magdalena M Vergara Greeno Rebeca R Baptiste Beverly A BA Sykora Peter P Liu Dong D Cordonnier Stephanie S Fang Evandro F EF Croteau Deborah L DL Mattson Mark P MP Bohr Vilhelm A VA

Aging cell 20160930 1

Alzheimer'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 ...[more]

PMID: 27686631

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Project description:Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, mostly idiopathic and with palliative treatment. Neuropathologically, it is characterized by intracellular neurofibrillary tangles of tau protein and extracellular plaques of amyloid ? peptides. The relationship between AD and neurogenesis is unknown, but two facts are particularly relevant. First, early aggregation sites of both proteinopathies include the hippocampal formation and the olfactory bulb (OB), which have been correlated to memory and olfactory deficits, respectively. These areas are well-recognized integration zones of newly-born neurons in the adult brain. Second, molecules, such as amyloid precursor protein (APP) and presenilin-1 are common to both AD etiology and neurogenic development. Adult neurogenesis in AD models has been studied in the hippocampus, but only occasionally addressed in the OB and results are contradictory. To gain insight on the relationship between adult neurogenesis and AD, this work analyzes neurogenesis, neurodegeneration, interneuron vulnerability, and amyloid-? involvement in the OB of an AD model. Control and double-transgenic mice carrying the APP and the presenilin-1 genes, which give rise amyloid ? plaques have been used. BrdU-treated animals have been studied at 16, 30, 43, and 56 weeks of age. New-born cell survival (BrdU), neuronal loss (using neuronal markers NeuN and PGP9.5), differential interneuron (calbindin-, parvalbumin-, calretinin- and somatostatin-expressing populations) vulnerability, and involvement by amyloid ? have been analyzed. Neurogenesis increases with aging in the granule cell layer of control animals from 16 to 43 weeks. No neuronal loss has been observed after quantifying NeuN or PGP9.5. Regarding interneuron population vulnerability: calbindin-expressing neurons remains unchanged; parvalbumin-expressing neurons trend to increase with aging in transgenic animals; calretinin-expressing neurons increase with aging in transgenic mice and decrease in control animals and neurogenesis is higher in control as compared to transgenic animals at given ages, finally; somatostatin-expressing neurons of transgenic mice decrease with aging and as compared to controls. Amyloid ? aggregates with aging in the granule cell layer, which may be related to the particular involvement of somatostatin-expressing cells.

Dataset Information

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

Publications

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

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