Research Description

Highlights of Major Accomplishments

• Demonstration that the neuronal toxicity of amyloid b-protein (Ab involves conversion to a fibrillar form binding to an Ab receptor (e.g., amyloid precursor protein [APP]), and activation of a downstream mechanism to apoptosis that involves caspase-12,
  
  
• Discovery that Down’s syndrome neurons abnormally process APP and generate high intracellular levels of a pathogenic form of Ab.

• Demonstration that presenilins modulate neuronal vulnerability to apoptosis by regulation of developmentally important signaling pathways.

3. Animal model of neurodegeneration in AD and DS

4. Biological functions of the presenilins and their role in brain development and familial AD

5. Mechanism by which apolipoprotein E predisposes to AD and the role of dietary factors in pathogenesis

6. Prototype drugs for treatment in AD and DS

1. Mechanism of Ab neurotoxicity in AD and DS

Since our initial description of the neurotoxic effects of Ab, we have made substantial progress in understanding the mechanism of toxicity. First, we showed that conversion of Ab to a fibrillar form is required for neurotoxicity. We then demonstrated that this structural change in the peptide results in high affinity binding to a subset of neuronal cell surface proteins. One Ab receptor is its normal cellular precursor, the amyloid precursor protein (APP). The interaction of A$ with APP may be a first step in the pathway of Ab toxicity, as neurons from APP-knockout mice are partially resistant to Ab neurotoxicity but not to other forms of toxicity. We also found that a novel endoplasmic reticulum-associated caspase, caspase-12, plays a role in the downstream effector phase of Ab neurotoxicity.

2. Mechanisms of neurodegeneration that underlie mental retardation and dementia in DS

Our laboratory has established a cortical culture model of DS in which DS neurons exhibit accelerated apoptosis relative to controls. To determine the role of APP in this neurodegenerative process, we investigated the metabolism of APP in DS and control cortical neurons. APP was abnormally processed in DS neurons, resulting in the generation of high intracellular levels of a pathogenic 42 amino acid form of Ab. We are in the process of identifying the enzyme that abnormally cleaves APP in DS neurons in order to define its role in the neurodegenerative process and to ascertain whether it is a potential therapeutic target.

3. Animal model of neurodegeneration in AD and DS

Previous attempts to establish an animal model of AD with APP-transgenic mice resulted in animals with amyloid plaque formation but little neurodegeneration. We demonstrated that this lack of neurodegeneration is likely to be due to a species barrier to Ab neurotoxicity by showing that microinjection of Ab in the aged primate brain results in marked neurodegeneration and pathological features of AD and DS. Moreover, the establishment of this animal model showed that Ab neurotoxicity is markedly age-dependent, possibly accounting for the age-dependence of neurodegeneration and dementia in AD and DS.

4. Biological functions of the presenilins and their role in brain development and familial AD

Mutations in the presenilin-1 gene are the most common cause of early-onset familial AD. We participated in the initial characterization of the presenilins by describing their localization and processing in neurons. We also defined major regulatory functions of presenilin-1 in the Notch and b-catenin signal transduction pathways which are perturbed by mutations associated with familial AD. In addition, we provided evidence that presenilins may modulate neuronal vulnerability to apoptosis through regulation of b-catenin signaling. The critical role of presenilins in the regulation of developmentally important signaling pathways raises the possibility that impaired presenilin function could contribute to mental retardation or developmental disabilities.

5. Mechanism by which apolipoprotein E predisposes to AD and the role of dietary factors in pathogenesis

The apolipoprotein E (apoE) 4 allele is the most common genetic risk factor for Alzheimer’s disease. We have shown that apoE may predispose to AD by stabilizing a pathogenic 42 amino acid form of the Ab protein. This effect of apoE appears to be modulated by dietary factors which influence apoE levels in the brain.

6. Prototype drugs for treatment in AD and DS

Using the in vitro and animal models that we have established, several potentially therapeutic agents that inhibit Ab neurotoxicity and the degeneration of DS neurons have been discovered. These compounds are currently under investigation..

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