Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease

Stover, Kurt R.; Campbell, Mackenzie A.; Winssen, Christine M. Van; Brown, Richard E.

doi:10.1016/j.bbr.2015.04.012

Cited by 152 publications

(123 citation statements)

References 38 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…In the 3XTg‐AD transgenic mouse model, accumulation of Aβ and earliest memory deficits were reported at 6 months of age, whereas elevation of both Aβ and tau was reported at 12 months of age [32]. We observe (Fig.…”

Section: Resultsmentioning

confidence: 54%

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Krishnan

Kayed

Taglialatela

2018

A&D Transl Res & Clin Interv

View full text Add to dashboard Cite

IntroductionPhospholipase D (PLD), a lipolytic enzyme that breaks down membrane phospholipids, is also involved in signaling mechanisms downstream of seven transmembrane receptors. Abnormally elevated levels of PLD activity are well-established in Alzheimer's disease (AD), implicating the two isoforms of mammalian phosphatidylcholine cleaving PLD (PC-PLD1 and PC-PLD2). Therefore, we took a systematic approach of investigating isoform-specific expression in human synaptosomes and further investigated the possibility of therapeutic intervention using preclinical studies.MethodsSynaptosomal Western blot analyses on the postmortem human hippocampus, temporal cortex, and frontal cortex of AD patient brains/age-matched controls and the 3XTg-AD mice hippocampus (mouse model with overexpression of human amyloid precursor protein, presenilin-1 gene, and microtubule-associated protein tau causing neuropathology progressing comparable to that in human AD patients) were used to detect the levels of neuronal PLD1 expression. Mouse hippocampal long-term potentiation of PLD1-dependent changes was studied using pharmacological approaches in ex vivo slice preparations from wild-type and transgenic mouse models. Finally, PLD1-dependent changes in novel object recognition memory were assessed following PLD1 inhibition.ResultsWe observed elevated synaptosomal PLD1 in the hippocampus/temporal cortex from postmortem tissues of AD patients compared to age-matched controls and age-dependent hippocampal PLD1 increases in 3XTg-AD mice. PLD1 inhibition blocked effects of oligomeric amyloid β or toxic oligomeric tau species on high-frequency stimulation long-term potentiation and novel object recognition deficits in wild-type mice. Finally, PLD1 inhibition blocked long-term potentiation deficits normally observed in aging 3XTg-AD mice.DiscussionUsing human studies, we propose a novel role for PLD1-dependent signaling as a critical mechanism underlying oligomer-driven synaptic dysfunction and consequent memory disruption in AD. We, further, provide the first set of preclinical studies toward future therapeutics targeting PLD1 in slowing down/stopping the progression of AD-related memory deficits as a complementary approach to immunoscavenging clinical trials that are currently in progress.

show abstract

Section: Resultsmentioning

confidence: 54%

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Krishnan

Kayed

Taglialatela

2018

A&D Transl Res & Clin Interv

View full text Add to dashboard Cite

show abstract

“…The novel object recognition test has been previously used to study memory in models of aging and its associated diseases (Fahlstrom et al, 2012, Stover et al, 2015). Our results support the notion that ketones may play an important role as neuro-protective signaling molecules (Newman and Verdin, 2014).…”

Section: Discussionmentioning

confidence: 99%

A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice

et al. 2017

View full text Add to dashboard Cite

Summary Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice.

show abstract

“…Other researchers [72–74] have found that spatial learning deficits demonstrated by differences in errors or search strategy do not always extend to distance travelled or latency to reach the escape box. As discussed in Refs.…”

Section: Discussionmentioning

confidence: 99%

Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits

Snider

Dziema

Aten

et al. 2016

Behavioural Brain Research

View full text Add to dashboard Cite

A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day.

show abstract

Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease

Cited by 152 publications

References 38 publications

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice

Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits

Contact Info

Product

Resources

About