Learning Decreases Aβ*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice

Billings, Lauren M.; Green, Kim N.; McGaugh, James L.; LaFerla, Frank M.

doi:10.1523/jneurosci.4800-06.2007

Cited by 126 publications

(117 citation statements)

References 50 publications

(58 reference statements)

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“…Similarly, Ab*56 has been associated with memory deficits in the 3xTg-AD mouse (which harbour the Swedish APP, P301L-t and PS1 M146V mutations), independent of Ab plaque formation. 36 The researchers observed that spatial training resulted in delayed Ab plaque deposition, reduced t-aggregation and reduction in Ab*56 levels. This training effect was most pronounced in young and middle-aged mice, as no effect was observed in aged animals, lending further support to the notion that the younger brain is more capable of handling AD-like lesions than the aged brain.…”

Section: Biology Of Ab In the Brain And Peripherymentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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Section: Biology Of Ab In the Brain And Peripherymentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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“…It is unclear how continuous P4 affects GSK-3␤, although our data predict that extended P4 exposure alters the balance of taurelevant kinase and phosphatase activities to yield a net decrease in pathological tau phosphorylation. Interestingly, previous studies have demonstrated that GSK-3␤-dependent regulation of tau hyperphosphorylation is related to behavioral performance in 3xTg-AD mice (Billings et al, 2007), which suggests a potentially important connection between the effects of progesterone on tau hyperphosphorylation and cognition in AD patients.…”

Section: Discussionmentioning

confidence: 97%

Progesterone and Estrogen Regulate Alzheimer-Like Neuropathology in Female 3xTg-AD Mice

Carroll¹,

Rosario²,

Chang³

et al. 2007

J. Neurosci.

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Estrogen depletion in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD), and estrogen-based hormonetherapymayreducethisrisk.However,theeffectsofprogesteronebothaloneandincombinationwithestrogenonADneuropathology remain unknown. In this study, we used the triple transgenic mouse model of AD (3xTg-AD) to investigate the individual and combined effects of estrogen and progesterone on ␤-amyloid (A␤) accumulation, tau hyperphosphorylation, and hippocampal-dependent behavioral impairments. In gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased A␤ accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogen on A␤accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.

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“…Behavioral studies have indicated further important components of the phenotype in separate lines of PDAPP mice including both age-related and age-independent deficits in spatial learning (Chen et al 2000;Dodart et al 2000). These and other important lines of transgenic mice carrying human mutations that occur in familial Alzheimer's disease show learning deficits in a variety of other cognitive tasks (Hsiao et al 1996;Chapman et al 1999;Kobayashi and Chen 2005;Billings et al 2007;Eriksen and Janus 2007).…”

mentioning

confidence: 99%

Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: Deficit in memory retrieval associated with increased sensitivity to interference?

Daumas¹,

Sandin²,

Chen³

et al. 2008

Learn. Mem.

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Two experiments were conducted to investigate the possibility of faster forgetting by PDAPP mice (a well-established model of Alzheimer’s disease as reported by Games and colleagues in an earlier paper). Experiment 1, using mice aged 13–16 mo, confirmed the presence of a deficit in a spatial reference memory task in the water maze by hemizygous PDAPP mice relative to littermate controls. However, after overtraining to a criterion of equivalent navigational performance, a series of memory retention tests revealed faster forgetting in the PDAPP group. Very limited retraining was sufficient to reinstate good memory in both groups, indicating that their faster forgetting may be due to retrieval failure rather than trace decay. In Experiment 2, 6-mo-old PDAPP and controls were required to learn each of a series of spatial locations to criterion with their memory assessed 10 min after learning each location. No memory deficit was apparent in the PDAPP mice initially, but a deficit built up through the series of locations suggestive of increased sensitivity to interference. Faster forgetting and increased interference may each reflect a difficulty in accessing memory traces. This interpretation of one aspect of the cognitive deficit in human mutant APP mice has parallels to deficits observed in patients with Alzheimer’s disease, further supporting the validity of transgenic models of the disease.

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Learning Decreases Aβ*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice

Cited by 126 publications

References 50 publications

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Progesterone and Estrogen Regulate Alzheimer-Like Neuropathology in Female 3xTg-AD Mice

Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: Deficit in memory retrieval associated with increased sensitivity to interference?

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