Effects of Neurotrophic Support and Amyloid-Targeted Combined Therapy on Adult Hippocampal Neurogenesis in a Transgenic Model of Alzheimer's Disease

Morrone, Christopher D.; Thomason, Lynsie A.M.; Brown, Mary Elizabeth; Aubert, Isabelle; McLaurin, JoAnne

doi:10.1371/journal.pone.0165393

Cited by 8 publications

(10 citation statements)

References 57 publications

(76 reference statements)

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“…To assess neurogenesis proliferation and survival, double immunofluorescent staining and cell counts of EdU co-localized with doublecortin (DCX), and of BrdU co-localized with neuronal nuclei (NeuN) were conducted, respectively (Supplementary material). One in every 10 hippocampal sections were sampled, starting from Bregma −2.28 mm, as previously reported (Morrone et al , 2016). Double staining immunofluorescence of tau with amyloid-β plaques was conducted to demonstrate interaction.…”

Section: Methodsmentioning

confidence: 99%

“…For pathological and electrophysiological assessments, we based our sample size on previous experience and published work (McLaurin et al , 2006; Morrone et al , 2016; Bazzigaluppi et al , 2018). In light of up to 20% variation in behavioural readouts, and ensuring power of at least 80% across all contrasts, we thus required 16 rats per group at a significance level of 5% for behavioural analyses to reach statistical significance.…”

Section: Methodsmentioning

confidence: 99%

“…Pattern separation involves the disambiguation between learned stimuli and novel stimuli into distinct neuronal networks, whereas executive functions consist of multiple high-level cognitive processes that drive rule generation and behavioural selection. These processes are essential to normal human behaviour, and are disrupted in Alzheimer’s disease and Alzheimer’s disease models (Lepousez et al , 2015; Morrone et al , 2016; Toda et al , 2018; Moreno-Jiménez et al , 2019).…”

Section: Introductionmentioning

confidence: 99%

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Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Morrone

Bazzigaluppi

Beckett

et al. 2019

Brain

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Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Morrone

Bazzigaluppi

Beckett

et al. 2019

Brain

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“…Likewise, increased proliferation has been observed in the DG from Tg9291 mice aged 9–12 months once amyloid deposition is established (Kolecki et al, 2008). Additionally, recent studies in APP models, harboring both the Swedish and Indiana mutations (Morrone, Thomason, Brown, Aubert, & McLaurin, 2016), have shown that proliferation is also increased in the hippocampus from young mice, and compromised at later stages of the disease. Similarly, hippocampal proliferation and neuronal differentiation increased in young J20 mice.…”

Section: Discussionmentioning

confidence: 99%

Cell proliferation and neurogenesis alterations in Alzheimer’s disease and diabetes mellitus mixed murine models

Hierro-Bujalance

Marco

Ramos-Rodríguez

et al. 2020

Journal of Neurochemistry

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The classic neuropathological features of Alzheimer's disease (AD) are accompanied by other complications, including alterations in adult cell proliferation and neurogenesis. Moreover recent studies have shown that traditional markers of the neurogenic process, such as doublecortin (DCX), may also be expressed in CD8+ T cells and ionized calcium‐binding adaptor molecule 1 (Iba1+) microglia, in the close proximity to senile plaques, increasing the complexity of the condition. Altered glucose tolerance, observed in metabolic alteratioins, may accelerate the neurodegenerative process and interfere with normal adult cell proliferation and neurogenesis. To further explore the role of metabolic disease in AD, we analyzed cell proliferation and neurogenesis using 5’‐bromo‐2’‐deoxyuridine and DCX immunohistochemistry in three different mouse models of AD and metabolic alterations: APP/PS1xdb/db mice, APP/PS1 mice on a long‐term high‐fat diet, and APP/PS1 mice treated with streptozotozin. As reported previously, an overall reduction in cell proliferation and neurogenesis was observed after streptozotocin administration. In contrast, an increase in cell proliferation and neurogenesis was detected in neurogenic niches in 14‐ and 26‐week‐old APP/PS1xdb/db mice, accompanied by a slight increase in cortical cell proliferation. While a similar trend was observed in animals on a high‐fat diet, differences were not statistically significant. We observed very few DCX+/CD8+ cells and no DCX+/Iba1+ cells were observed in the close proximity to senile plaques in any of the groups. Interestingly, metabolic parameters such as body weight and glucose and insulin levels were identified as reliable predictors of cell proliferation and neurogenesis in APP/PS1xdb/db mice. Furthermore, metabolic parameters were also associated with altered Aβ levels in the cortex and hippocampus of APP/PS1xdb/db mice. Altogether, our data suggest that metabolic disease may also interfere with central complications in AD.

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“…Further, sI prevents tau hyperphosphorylation (Jin and Selkoe, 2015). These potentially beneficial effects have prompted development of sI and close sI analogs as potential treatments for AD/ADRD (Salloway et al, 2011;Morrone et al, 2016;Lee et al, 2017;Liu et al, 2018). A possible mechanism to explain the low sI signal in supraphysiologic-dose AAS users is that its synthetic enzyme, inositol epimerase, which converts myo-inositol to sI, may be inhibited by AAS.…”

Section: Supraphysiologic-dose Aas Exposures Are Associated With Neurmentioning

confidence: 99%

Supraphysiologic-dose anabolic–androgenic steroid use: A risk factor for dementia?

Kaufman

Kanayama

Hudson

et al. 2019

Neuroscience & Biobehavioral Reviews

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Supraphysiologic-dose anabolic-androgenic steroid (AAS) use is associated with physiologic, cognitive, and brain abnormalities similar to those found in people at risk for developing Alzheimer's Disease and its related dementias (AD/ADRD), which are associated with high brain β-amyloid (Aβ) and hyperphosphorylated tau (tau-P) protein levels. Supraphysiologic-dose AAS induces androgen abnormalities and excess oxidative stress, which have been linked to increased and decreased expression or activity of proteins that synthesize and eliminate, respectively, Aβ and tau-P. Aβ and tau-P accumulation may begin soon after initiating supraphysiologic-dose AAS use, which typically occurs in the early 20s, and their accumulation may be accelerated by other psychoactive substance use, which is common among non-medical AAS users. Accordingly, the widespread use of supraphysiologic-dose AAS may increase the numbers of people who develop dementia. Early diagnosis and correction of sex-steroid level abnormalities and excess oxidative stress could attenuate risk for developing AD/ADRD in supraphysiologic-dose AAS users, in people with other substance use disorders, and in people with low sex-steroid levels or excess oxidative stress associated with aging.

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Effects of Neurotrophic Support and Amyloid-Targeted Combined Therapy on Adult Hippocampal Neurogenesis in a Transgenic Model of Alzheimer's Disease

Cited by 8 publications

References 57 publications

Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Cell proliferation and neurogenesis alterations in Alzheimer’s disease and diabetes mellitus mixed murine models

Supraphysiologic-dose anabolic–androgenic steroid use: A risk factor for dementia?

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