Towards a Circuit-Level Understanding of Hippocampal CA1 Dysfunction in Alzheimer's Disease Across Anatomical Axes

Masurkar, Arjun V.

doi:10.4172/2161-0460.1000412

Cited by 45 publications

(38 citation statements)

References 88 publications

(99 reference statements)

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“…The latter is consistent with our previous observation reporting a downregulation of PARP-1 positive staining in the hippocampal CA1 region in AD compared to controls [22]. These results are also consistent with previous observations in which CA1- subiculum was found to be involved early in spatiotemporal progression of AD atrophy and hypometabolism, and postulated to be particularly vulnerable due to high synaptic output and metabolic demand [34]. In this study, we did not find a decrease in the percentage of PARP-1 positive nucleoli in the CA4 region in AD, in contrast to our previously reported findings.…”

Section: Discussionsupporting

confidence: 93%

Evidence for Decreased Nucleolar PARP-1 as an Early Marker of Cognitive Impairment

et al. 2019

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Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that regulates gene expression through poly(ADP)-ribosylation, resulting in the loosening of chromatin structure. PARP-1 enzymatic activity has been shown to be necessary for the expression of several genes required for memory formation and consolidation. Previously, we showed that nucleolar PARP-1 is significantly decreased in hippocampal pyramidal cells in Alzheimer's disease (AD). We proposed that the displacement of PARP-1 from the nucleolus results in downregulation of new rRNA expression and ribosome biogenesis, leading to cognitive impairment. To further investigate the relationship between nucleolar PARP-1 and memory impairment, we examined PARP-1 expression in the hippocampi of individuals with mild cognitive impairment (MCI) compared to control and AD cases. We used immunohistochemical techniques to examine the nucleolar distribution of PARP-1 in the Cornu Ammonis (CA region) of the hippocampus. PARP-1 positive cells were then scored for the presence or absence of PARP-1 in the nucleolus. We found a significant decrease of PARP-1 staining in the nucleolar compartment of hippocampal pyramidal cells in MCI compared with Control and AD. When the four CA (CA1-4) regions were considered separately, only the CA1 region showed significant differences in nucleolar PARP-1 with Control > AD > MCI cases. Categorization of nucleolar PARP-1 into “distinct” and “diffuse” groups suggest that most of the changes occur within the distinct group. In addition, measurements of the nucleolar diameter of nucleolar PARP-1 positive cells in CA2 and CA4 showed Control > MCI. Thus, MCI cases had a lower percentage of PARP-1 nucleolar positive cells in CA1 and smaller nucleolar diameters in CA2 and CA4, compared to Control. Our data suggest that disruption of nucleolar form and function is an early and important step in the progression of cognitive impairment.

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Section: Discussionsupporting

confidence: 93%

Evidence for Decreased Nucleolar PARP-1 as an Early Marker of Cognitive Impairment

et al. 2019

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“…The hippocampus might have discrete functional domains along its regions and subregions that affect learning and memory processes, so region-specific differences could also be observed in the deterioration of the LTP during AD progression. Several studies have reported differences in LTP induction and amplitude within the dorsal and ventral parts of the CA1 region in rodents [22]. While some studies using Tg AD mouse models [6,7] have indicated the relevance of DG-related impaired LTP and memory deficits in the AD rodent brain, our data indicate that the CA1 region might be, at least, equally critical in the process of the memory decline in AD.…”

Section: Resultscontrasting

confidence: 49%

Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

et al. 2020

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Alzheimer’s disease (AD) is a complex and chronic neurodegenerative disorder that involves a progressive and severe decline in cognition and memory. During the last few decades a considerable amount of research has been done in order to better understand tau-pathology, inflammatory activity and neuronal synapse loss in AD, all of them contributing to cognitive decline. Early hippocampal network dysfunction is one of the main factors associated with cognitive decline in AD. Much has been published about amyloid-beta1-42 (Aβ1-42)-mediated excitotoxicity in AD. However, increasing evidence demonstrates that the remodeling of the inhibitory gamma-aminobutyric acid (GABAergic) system contributes to the excitatory/inhibitory (E/I) disruption in the AD hippocampus, but the underlying mechanisms are not well understood. In the present study, we show that hippocampal injection of Aβ1-42 is sufficient to induce cognitive deficits 7 days post-injection. We demonstrate using in vitro whole-cell patch-clamping an increased inhibitory GABAergic tonic conductance mediated by extrasynaptic type A GABA receptors (GABAARs), recorded in the CA1 region of the mouse hippocampus following Aβ1-42 micro injection. Such alterations in GABA neurotransmission and/or inhibitory GABAARs could have a significant impact on both hippocampal structure and function, causing E/I balance disruption and potentially contributing to cognitive deficits in AD.

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“…One circuit that might be important to evaluate is the projection from the lateral entorhinal cortex to the CA1 region of the HPC. The CA1 subregion shows intrinsic and circuit heterogeneity that may underlie the involvement of this structure in AD-associated behavioral pathologies (Masurkar, 2018); thus, subregional and circuit analyses have potential to identify specific anatomical substrates of alcohol’s impact on AD. Given the involvement of these brain regions in the onset of AD-like pathology, attenuating activity of this pathway may block or enhance disease state.…”

Section: Discussionmentioning

confidence: 99%

Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease

Hoffman

Faccidomo

Kim

et al. 2019

International Review of Neurobiology

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer’s pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.

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Towards a Circuit-Level Understanding of Hippocampal CA1 Dysfunction in Alzheimer's Disease Across Anatomical Axes

Cited by 45 publications

References 88 publications

Evidence for Decreased Nucleolar PARP-1 as an Early Marker of Cognitive Impairment

Evidence for Decreased Nucleolar PARP-1 as an Early Marker of Cognitive Impairment

Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease

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