Cognitive Decline in Preclinical Alzheimer’s Disease: Amyloid-Beta versus Tauopathy

Huber, Colin M.; Yee, Connor; May, Taylor; Dhanala, Apoorva; Mitchell, Cassie S.

doi:10.3233/jad-170490

Cited by 101 publications

(76 citation statements)

References 105 publications

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“…Spatial Learning. Results showed that 3xTg-AD mice exhibited a deficit in acquisition of spatial learning that was not altered by alcohol exposure (Figure 5A, left), which is consistent with known performance of this mouse strain (Huber et al, 2018). Three-way RM-ANOVA (genotype x alcohol x trial) identified a significant main effect of trial [F (2.006, 24.07) = 3.511, P=0.0458] and genotype [F (1, 12) = 7.841, P=0.02].…”

Section: Alcohol-induced Deficit In Spatial Memory In 3xtg-ad Micesupporting

confidence: 78%

“…These neuropathies are associated with behavioral deficits including cognitive decline and altered emotional processing that are characteristic of AD (Filali et al, 2012;Pietropaolo et al, 2014;Romano et al, 2014;Webster et al, 2014). A meta-analysis of 51 studies using the 3xTg-AD mice found that Tau and Aβ (40 and 42) expression showed a strong association with impaired cognitive function (Huber et al, 2018). Importantly, it is highly significant that 3xTg-AD mice express Tau, APP, and PSEN-1, which our neuroproteomic studies have shown are the main modulators of alcohol-sensitive protein networks within the AMY (Salling et al, 2016) and PFC of mice (Figure 1).…”

Section: Translational Approach: Selection Of the Triple-transgenic Mmentioning

confidence: 99%

“…As noted above, the NIA-AA Research Framework recommends a focus on these markers to enable a more accurate characterization and understanding of neural events that lead to AD-related cognitive and behavioral impairment (Jack et al, 2018). A recent meta-analysis of 51 peer-reviewed studies shows that neural expression of Aβ (40 and 42) and pTau (AT8ser 181 and ser 199) exhibit strong associations with cognitive decline in the well-validated 3xTg-AD mouse model of AD that expresses human MAPT, APP, and PSEN-1 transgenes (Huber et al, 2018). Taken together with our neuroproteomic data show that alcohol-sensitive protein networks in the PFC and AMY are downstream of the MAPT, APP, and PSEN-1, this provides a strong rationale for evaluating the impact of alcohol intake on NIA-AA biomarkers in 3xTg-AD mice.…”

Section: Nia-aa Biomarker Analysis In Specific Brain Regions Of 3xtg-mentioning

confidence: 99%

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Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Hoffman

Faccidomo

Kim

et al. 2019

Preprint

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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 non-dependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology.We first evaluated the impact of voluntary 24-h, 2-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 ADassociated 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 wildtype 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 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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Section: Alcohol-induced Deficit In Spatial Memory In 3xtg-ad Micesupporting

confidence: 78%

Section: Translational Approach: Selection Of the Triple-transgenic Mmentioning

confidence: 99%

Section: Nia-aa Biomarker Analysis In Specific Brain Regions Of 3xtg-mentioning

confidence: 99%

See 1 more Smart Citation

Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Hoffman

Faccidomo

Kim

et al. 2019

Preprint

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“…10,13,14 Such observations are of high importance since, contrary to amyloid plaques, neurofibrillary tangles (NFTs) are well correlated with cognitive impairment both in humans 15 and in animal models. 16 Among the genes described to genetically interact with Tau in Drosophila, BIN1 was further described to directly interact with the Tau protein by NMR spectroscopy using recombinant proteins, in vitro glutathion S-transferase (GST) pull-down from HEK293 lysates, as well as reciprocal co-immunoprecipitation from mouse brain synaptosome homogenates. 17 In addition, a genome-wide significant functional risk variant in the vicinity of BIN1 has been associated with Tau loads (but not with Aβ loads) in AD brains.…”

Section: Introductionmentioning

confidence: 99%

BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr³⁴⁸ phosphorylation

Sartori

Mendes

Desai

et al. 2018

Preprint

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For molecular and cellular experiments in neurons and in human brain samples AbstractThe bridging integrator 1 gene (BIN1) is a major genetic risk factor for Alzheimer's disease (AD). In this report, we investigated how BIN1-dependent pathophysiological processes might be associated with Tau. We first generated a cohort of control and transgenic mice either overexpressing human MAPT (TgMAPT) or both human MAPT and BIN1 (TgMAPT;TgBIN1), which we followed-up from 3 to 15 months. In TgMAPT;TgBIN1 mice short-term memory deficits appeared earlier than in TgMAPT mice; however -unlike TgMAPT mice -TgMAPT;TgBIN1 mice did not exhibit any long-term or spatial memory deficits for at least 15 months. After sacrifice of the cohort at 18 months, immunohistochemistry revealed that BIN1 overexpression prevents both Tau mislocalization and somatic inclusion in the hippocampus, where an increase in BIN1-Tau interaction was also observed. We then sought mechanisms controlling the BIN1-Tau interaction. We developed a high-content screening approach to characterize modulators of the BIN1-Tau interaction in an agnostic way (1,126 compounds targeting multiple pathways), and we identified -among others -an inhibitor of Calcineurin, a Ser/Thr phosphatase. We determined that Calcineurin dephosphorylates BIN1 on a Cyclin-dependent kinase phosphorylation site at T348, promoting the open conformation of the neuronal BIN1 isoform.Phosphorylation of this site increases the availability of the BIN1 SH3 domain for Tau interaction, as demonstrated by nuclear magnetic resonance experiments and in primary neurons. Finally, we observed that the levels of the neuronal BIN1 isoform were decreased in AD brains, whereas phospho-BIN1(T348):BIN1 ratio was increased, suggesting a compensatory mechanism. In conclusion, our data support the idea that BIN1 modulates the AD risk through an intricate regulation of its interaction with Tau. Alteration in BIN1 expression or activity may disrupt this regulatory balance with Tau and have direct effects on learning and memory.

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“…However, the mechanisms linking these two key players remain obscure. 28 Recent study suggests that the SNS may play a role. 29…”

Section: Introductionmentioning

confidence: 99%

The Danger of Being Too Sympathetic: Norepinephrine in Alzheimer's Disease and Graying of Hair

Mendelsohn

Larrick

2020

Rejuvenation Research

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Although alterations in the sympathetic nervous system (SNS) with age have been reported, and serious degenerative diseases of the autonomic nervous system such as multiple system atrophy are more likely to strike older people, connections between dysregulated adrenergic receptors and age-associated diseases and phenotypes have not been well studied. Two recent reports suggest that SNS may be more closely connected than previously appreciated. First, low nanomolar concentrations of Alzheimer's disease (AD)-associated Ab42-amyloid oligomers alter signaling by SNS neurotransmitter norepinephrine (NE) to sufficiently activate kinase GSK3b to hyperphosphorylate tau, a key mediator of neurotoxicity in AD. Connecting beta-amyloid to tau in AD has been a key quest in understanding AD and developing therapeutics. The a 2 adrenergic receptor inhibitory drug idazoxan reduces GSK3b activity and tau phosphorylation in AD mice with improved cognitive function, even in the presence of betaamyloid deposits. In this study, SNS activation in the brain coupled with problematic Ab42-amyloid oligomers result in serious consequences that can be ameliorated by reducing SNS signaling. A second example of the detrimental effects of increased SNS signaling is the premature graying of hair in response to stress. Secretion of NE resulting from stress causes differentiation of most hair pigment melanocyte stem cells (MeSCs) into melanocytes, rapidly depleting the hair follicle of pigment-producing cells as mature melanocytes undergo apoptosis and MeSCs are eventually eliminated. Blockade of NE SNS signaling preserves hair coloration in stressed animals. Increased SNS activation has serious apparently irreversible effects on homeostasis in both situations. Although neither report directly addresses aging, given that AD and the loss of hair pigmentation have strong age associations, it is of interest to better understand the role that SNS has in promoting age-associated phenotypes generally and determine if tuning the SNS through drug-mediated attenuation of SNS signaling may be of medical benefit.

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Cognitive Decline in Preclinical Alzheimer’s Disease: Amyloid-Beta versus Tauopathy

Cited by 101 publications

References 105 publications

Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr³⁴⁸ phosphorylation

The Danger of Being Too Sympathetic: Norepinephrine in Alzheimer's Disease and Graying of Hair

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Cognitive Decline in Preclinical Alzheimer’s Disease: Amyloid-Beta versus Tauopathy

Cited by 101 publications

References 105 publications

Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation

The Danger of Being Too Sympathetic: Norepinephrine in Alzheimer's Disease and Graying of Hair

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BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr³⁴⁸ phosphorylation