Center for Cellular Neurobiology and Neurodegeneration Research

Lowell, MA, United States

Center for Cellular Neurobiology and Neurodegeneration Research

Lowell, MA, United States
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Lortie J.J.,Knox College | Remington R.,UMass Lowell | Hoffmann H.,Knox College | Shea T.B.,UMass Lowell | Shea T.B.,Center for Cellular Neurobiology and Neurodegeneration Research
International Journal of Alzheimer's Disease | Year: 2012

Individuals with MCI declined in performance over 6 months in the Clock-drawing (Clox 1) and the WAIS Digit Span tests, but not in the Dementia Rating Scale (DRS). Individual performance on Clox 1 and Digit Span did not correlate after 6 months. Performance on the Digit Span Test also did not correlate with the DRS, but performance on Clox 1 correlated with the DRS. Performance in Clox 1 was, therefore, not a predictor of performance in the Digit Span Test. These findings support the use of a test battery containing the Digit Span test to detect and track cognitive decline in MCI. © 2012 Jevin Jay Lortie et al.


Lee S.,Center for Cellular Neurobiology and Neurodegeneration Research | Zemianek J.,Center for Cellular Neurobiology and Neurodegeneration Research | Shea T.B.,Center for Cellular Neurobiology and Neurodegeneration Research
Journal of Alzheimer's Disease | Year: 2013

Alzheimer's disease is accompanied by the accumulation of amyloid-β (Aβ) and the microtubule-associated protein tau. Aβ toxicity is dependent upon its form as well as concentration. Soluble Aβ oligomers, rather than the fibrillar forms that comprise senile plaques, represent the toxic form and are correlated with the extent of dementia. Since soluble Aβ perturbs synaptic function, we examined the impact of exogenously applied Aβ on signaling in neurons cultured on multi-electrode arrays. We observed that subcytotoxic levels (10 nm-5 μM) of human Aβ1-42 perturbed synaptic transmission within hours. This perturbation suggests that mild cognitive problems, perhaps undetected by traditional clinical approaches, can accompany critical accumulation of Aβ. This effect was prevented by the calcium chelator BAPTA, indicating a requirement for calcium for inhibition of signaling by Aβ. Aβ-induced inhibition of signaling was not prevented by application of MK-801 or nimodipine (antagonists of the NMDA receptor and L-type voltage-sensitive calcium channel, respectively) suggesting that Aβ may induce influx by either channel, or additional channels, or that neurons contained sufficient calcium to mediate the impact of Aβ. Signaling returned to original levels within 120 h after administration of a single dosage of Aβ, or within 24 h after replacement of medium with fresh medium lacking Aβ, suggesting that intervention to reduce Aβ levels at their first appearance may prevent permanent neurotoxicity. © 2013 - IOS Press and the authors. All rights reserved.


Lee S.,Center for Cellular Neurobiology and Neurodegeneration Research | Lemere C.A.,Brigham and Women's Hospital | Frost J.L.,Brigham and Women's Hospital | Shea T.B.,Center for Cellular Neurobiology and Neurodegeneration Research
Journal of Alzheimer's Disease | Year: 2012

S-adenosyl methionine (SAM) contributes to multiple pathways in neuronal homeostasis, several of which are compromised in age-related neurodegeneration and Alzheimer's disease. Dietary supplementation of transgenic mice with SAM maintained acetylcholine levels, cognitive performance, oxidative buffering capacity, and phosphatase activity, and reduced aggression, calcium influx, endogenous PS-1 expression, γ-secretase activity, and levels of amyloid-β (Aβ) and phospho-tau. Herein, we examined whether or not SAM could delay neuropathology in 3xTg-AD mice, which harbor mutant genes for human AβPP, PS-1 and tau. Mice received a standard AIN-76 diet with or without SAM (100 mg/kg diet) for 1 month commencing at 10 months of age or for 3 months commencing at 12.5 months of age; mice were sacrificed and examined for Aβ and tau neuropathology at 11 and 15.5 months of age, respectively. SAM supplementation reduced hippocampal intracellular AβPP/Aβ and phospho-tau immunoreactivity to a similar extent at both sampling intervals. Supplementation reduced the number of extracellular Aβ deposits by 80% (p < 0.01) at 11 months of age after 1 month of treatment but only by 24% (p < 0.34) at 15.5 months of age after 3 months of treatment. As anticipated, neurofibrillary tangles were not observed in mice at these young ages; however, supplementation reduced levels of phospho-tau and caspase-cleaved tau within Sarkosyl-insoluble preparations in mice at 15.5 months of age. These limited analyses indicate that SAM can modulate the time course of AD neuropathology, and support further long-term analyses. © 2012 - IOS Press and the authors. All rights reserved.


Chan A.,Center for Cellular Neurobiology and Neurodegeneration Research | Shea T.B.,Center for Cellular Neurobiology and Neurodegeneration Research
Journal of Alzheimer's Disease | Year: 2010

The presence of one or more copies of the E4 allele of apolipoprotein E (ApoE) is strongly associated with of Alzheimer's disease (AD). The impact of E4 on neurodegeneration is potentiated by dietary oxidative challenge. Our prior studies in transgenic mice demonstrate that, in the face of dietary oxidative challenge, E3 does not provide any further protection than E4 or lack of murine ApoE for aggression, oxidative damage, presenilin-1 expression, and γ-secretase activity, and provides only partial reduction in phospho-tau levels. Extrapolation of these findings to the human condition leads us to hypothesize that the E3 allele may not provide sufficient neuroprotection under conditions of dietary compromise and/or oxidative challenge. Epidemiological evidence is consistent with this possibility. The E3 allele is approximately half as effective compared to E2 at buffering the impact of a single E4 allele. In addition, the risk of AD increases linearly for the genotypes E2/2, E2/3, and E3/3. It has been proposed that that clinical manifestation of AD may in some cases require the convergence of 2 or more risk factors. We hypothesize that the combined impact of dietary oxidative stress and either the ApoE3 or E4 genotype represents one such condition. © 2010 IOS Press.


Shea T.B.,Center for Cellular Neurobiology and Neurodegeneration Research | Rogers E.,Center for Cellular Neurobiology and Neurodegeneration Research | Remington R.,Center for Cellular Neurobiology and Neurodegeneration Research
Journal of Alzheimer's Disease | Year: 2012

Alzheimer's disease (AD) has no cure or nullifying pharmacological interventions. Nutritional supplementation represents a systemic approach that in some studies has provided benefit and has augmented pharmacological approaches. However, additional studies report no benefit of supplementation. We review herein how studies of nutrition on dementia, including those combining nutrition and dementia, are inherently compromised. We also review studies with mice, which demonstrate that nutritional supplementation can alleviate multiple genetic risk factors for AD. An individual diagnosed with AD has by definition undergone considerable cognitive decline; anticipating restoration/maintenance of cognitive performance following nutritional supplementation alone may be misdirected. Nutrition declines in aging, and even more so in AD. While optimization of nutrition should ideally be initiated well before any cognitive decline, we present evidence that the systemic benefit alone of nutritional supplementation at the very minimum warrants initiation along with pharmacological intervention. © 2012-IOS Press and the authors. All rights reserved.


Shea T.B.,Center for Cellular Neurobiology and Neurodegeneration Research | Remington R.,Framingham State University
Journal of Neural Transmission | Year: 2012

The ongoing debate as to whether we are or are not early enough in treatment for Alzheimer's disease presents distinct vantage points. Points expressed range from stressing the need for early preventive measures to highlighting the failure of "alternative" therapies, and concluding that we are unfortunately doing all that we can at present. Herein, we stress the worth of nutritional intervention, and review why such studies are often inherently compromised. We conclude that considerable education is needed to advance lifestyle modifications early enough to obtain their optimal effect, and instead of positioning "classical" interventions against "alternative" interventions, the combinations of both may impart maximal benefit. The introduction of novel detection methods at the earliest indications of cognitive impairment may provide a window of opportunity for initiation of preventative approaches. © 2012 Springer-Verlag.


PubMed | Center for Cellular Neurobiology and Neurodegeneration Research
Type: Journal Article | Journal: Journal of Alzheimer's disease : JAD | Year: 2012

S-adenosyl methionine (SAM) contributes to multiple pathways in neuronal homeostasis, several of which are compromised in age-related neurodegeneration and Alzheimers disease. Dietary supplementation of transgenic mice with SAM maintained acetylcholine levels, cognitive performance, oxidative buffering capacity, and phosphatase activity, and reduced aggression, calcium influx, endogenous PS-1 expression, -secretase activity, and levels of amyloid- (A) and phospho-tau. Herein, we examined whether or not SAM could delay neuropathology in 3xTg-AD mice, which harbor mutant genes for human APP, PS-1 and tau. Mice received a standard AIN-76 diet with or without SAM (100 mg/kg diet) for 1 month commencing at 10 months of age or for 3 months commencing at 12.5 months of age; mice were sacrificed and examined for A and tau neuropathology at 11 and 15.5 months of age, respectively. SAM supplementation reduced hippocampal intracellular APP/A and phospho-tau immunoreactivity to a similar extent at both sampling intervals. Supplementation reduced the number of extracellular A deposits by 80% (p < 0.01) at 11 months of age after 1 month of treatment but only by 24% (p < 0.34) at 15.5 months of age after 3 months of treatment. As anticipated, neurofibrillary tangles were not observed in mice at these young ages; however, supplementation reduced levels of phospho-tau and caspase-cleaved tau within Sarkosyl-insoluble preparations in mice at 15.5 months of age. These limited analyses indicate that SAM can modulate the time course of AD neuropathology, and support further long-term analyses.

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