Reversible memory loss in a mouse model of Alzheimer's disease

Department of Neurology, University of Minnesota, Minneapolis 55455, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2002; 22(15):6331-5.
Source: PubMed


Alzheimer's disease (AD) is a neurodegenerative condition, believed to be irreversible, characterized by inexorable deterioration of memory and intellect, with neuronal loss accompanying amyloid plaques and neurofibrillary tangles. In an amyloid precursor protein transgenic mouse model, Tg2576, little or no neuronal loss accompanies age-related memory impairment or the accumulation of Abeta, a 40-42 aa polypeptide found in plaques. Recently, we have shown inverse correlations between brain Abeta and memory in Tg2576 mice stratified by age (Westerman et al., 2002). Broadening the age range examined obscured this relationship, leading us to propose that small, soluble assemblies of Abeta disrupt cognitive function in these mice. Here we show that memory loss can be fully reversed in Tg2576 mice using intraperitoneally administered BAM-10, a monoclonal antibody recognizing the N terminus of Abeta. The beneficial effect of BAM-10 was not associated with a significant Abeta reduction, but instead eliminated the inverse relationship between brain Abeta and memory. We postulate that BAM-10 acts by neutralizing Abeta assemblies in the brain that impair cognitive function. Our results indicate that a substantial portion of memory loss in Tg2576 mice is not permanent. If these Abeta assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients.

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    • "In the past few years, different therapeutical approaches have been performed to modulate the amyloid brain depositions in APP-transgenic mice, including restricted administration of pharmaceutical agents [20], rich cholesterol diet [21], caloric diet [22], and intensive exercise [23]; however, Aí µí»½-based immunotherapy has been shown to be the most promising research field in reducing amyloid loads [24] [25] [26] [27] [28] and reversing memory deficits [9] [10] [29] in AD mouse models. Both active (Aí µí»½ peptides) and passive (Aí µí»½-specific antibodies) immunizations have been reported to achieve a certain degree of efficiency in reducing brain Aí µí»½ deposits in AD mouse models [30]. "

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    • "Implications for neural repair: A priority issue in contemporary neuroscience concerns the degree to which indigent repair mechanisms and neuroplasticity may reverse CNS damage after offending stimuli have dissipated. Evidence of spontaneous lesion reversibility, neuroplasticity and neurological recovery has been documented in APP transgenic mouse models of AD (Kotilinek et al., 2002), mutant tau-driven models of AD and frontotemporal dementia (Sydow et al., 2011), the MPTP mouse model of PD (Schmidt and Ferger, 2001), rodent models of Huntington disease (Yamamoto et al., 2000) and several spinocerebellar degeneration mimics (Boy et al., 2009). These remarkable reports suggest that clinically-relevant neuroregeneration may be invoked in a broad spectrum of neurodegenerative disorders following interruption of the salient pathological pathways. "

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    • "Based on the results obtained in the active immunization work, antibodies were developed against the N-terminus of the Aβ protein for direct injection. Treatment of APPtg mouse models of AD with the antibodies showed significant reductions in CNS Aβ and reversed memory deficits in object recognition and Morris water maze (Dodart et al., 2002; Kotilinek et al., 2002; Bard et al., 2003; Buttini et al., 2005). "
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    ABSTRACT: Alzheimer's disease (AD) is an incurable, progressive, neurodegenerative disorder affecting over 5 million people in the US alone. This neurological disorder is characterized by widespread neurodegeneration throughout the association cortex and limbic system caused by deposition of Aβ resulting in the formation of plaques and tau resulting in the formation of neurofibrillary tangles. Active immunization for Aβ showed promise in animal models of AD; however, the models were unable to predict the off-target immune effects in human patients. A few patients in the initial trial suffered cerebral meningoencephalitis. Recently, passive immunization has shown promise in the lab with less chance of off-target immune effects. Several trials have attempted using passive immunization for Aβ, but again, positive end points have been elusive. The next generation of immunotherapy for AD may involve the marriage of anti-Aβ antibodies with technology aimed at improving transport across the blood-brain barrier (BBB). Receptor mediated transport of antibodies may increase CNS exposure and improve the therapeutic index in the clinic.
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