Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease, which demonstrates positive (protein accumulation) and negative (neuronal loss) lesions. Despite this complexity, much of the research effort has been directed to the elucidation of a limited number of pathways involved in the positive lesions, such as the amyloid cascade. Unfortunately this work has so far failed to yield effective treatment options. Distinct programmed cell death (PCD) cascades contribute to neuronal cell loss in AD. Postmortem studies have demonstrated activation of caspase-dependent and independent apoptotic pathways, as well disruption of autophagic regulation. However, studies have produced conflicting results about the involvement of each of these pathways in AD pathogenesis, and their interactions with the positive lesions.
One of the main limitations of PCD studies in is the difficulty in obtaining human brains. Postmortem specimens typically derive from individuals with more advanced AD, and by this time most of the neurons have already been lost. Our goal is to quantitatively identify representative markers of apoptotic and autophagic signaling pathways in nuclei showing early vulnerability to AD (dorsal raphe nucleus and locus coeruleus) across progressive disease stages, and investigate how these interact with neurofibrillary tangle burden. This study will make use of a large unique collection of well-characterized human brains which are readily available and already processed. We apply a combination of state-of-the-art neuropathological methods, including computer-assisted 3D reconstruction and multiple label immunohistochemistry, in a difficult-to-obtain, well-characterized sample set, to clarify which PCD pathways are relevant in early AD and investigate their interactions with neurofibrillary changes. Characterizing which PCD pathways are relevant in AD most vulnerable sites and their relation to protein accumulation is critical if we are to identify and test potential therapies to enhance neuronal survival. Once this knowledge produced by this study is embedded in the current etiopathogenic schemes, animal models created to recapitulate these changes can be employed to develop strategies to detect and stabilize AD process before the cognitive changes appear, thus decreasing the economic and societal burden of AD.
This study is funded by the Alzheimer's Association