Individuals at risk of Alzheimer?s disease (AD) undergo a long, asymptomatic phase of disease progression that is characterized by the gradual accumulation of pathology in the absence of apparent cognitive deficit. Down syndrome (DS) patients represent a population at high risk of AD with complete penetrance of AD pathology in the majority of DS subjects, making DS an outstanding natural genetic model for the study of neuropathological mechanisms of AD and for identifying potential AD biomarkers. Given the current limitations in reliable early diagnostic tools, the discovery of biomarkers signalling the evolution of Alzheimer?s disease pathology in individuals at risk, including those with DS, is of utmost clinical relevance. The overall goal of the current proposal is to investigate novel, uncharacterized biomarkers at the earliest preclinical stages of AD in DS. To achieve this goal, a collaborative effort will integrate data from post-mortem brain studies, primary human cell cultures studies, and biological fluids (plasma and CSF) studies in a large well-characterized cohort of DS and matched control subjects. The central hypothesis of the proposal is that the early accumulation of intracellular amyloid beta peptide (A?) in DS brains will induce CNS inflammation accompanied by NGF metabolic dysfunction prior to extracellular amyloid plaque deposition. Furthermore, the CNS compromise of NGF metabolism should be detected in DS body fluids at ?incipient? stages of the AD pathology, before the presentation of overt dementia. To test the stated hypothesis, three Specific Aims will be accomplished:
Aim 1 : To explore the occurrence of a CNS pro-inflammatory process and NGF dysfunction throughout the lifespan in DS. Using post-mortem DS brains at different ages, the appearance of inflammation and NGF dysfunction in DS will be investigated to temporally reconstruct the evolution of AD pathogenesis.
Aim 2 : To investigate molecular mechanisms that link early AD pathology in DS with neuroinflammation and NGF metabolic dysfunction using fetal human primary cortical cultures. These studies will complement Aims 1 and 3 and will elucidate molecular pathways underlying early AD pathogenesis.
Aim 3 : To analyze the expression of A?, tau, NGF-related and inflammatory markers in matched plasma and CSF samples from DS subjects across the lifespan. These studies will test whether markers investigated in Aims- 1 and -2 are reflected in matched plasma and CSF samples from DS versus control subjects. This multi-PI multidisciplinary proposal will reveal fundamental molecular pathobiological mechanisms for AD in DS, it will identify biomarkers, and it will assist in the prediction of the onset and trajectory of dementia. In addition, the planned studies will likely lead to the identification of novel therapeutic targets in both DS individuals and sporadic AD populations.
The Role of Inflammation and NGF Dysfunction in the Evolution of Alzheimer?s Disease Pathology in Down syndrome NARRATIVE The main goal of the current proposal is to investigate novel, uncharacterized biomarkers at the earliest preclinical stages of Alzheimer?s disease in Down syndrome. This goal will be accomplished via testing the hypothesis that the early accumulation of intracellular A? in DS brains will induce CNS inflammation accompanied by NGF metabolic dysfunction prior to extracellular amyloid plaque deposition and that NGF metabolic dysfunction markers should be detected in body fluids at ?incipient? stages of the AD pathology. The proposal will integrate data from (1) post-mortem brain studies (Aim-1) that will explore the occurrence of a CNS pro-inflammatory process and NGF dysfunction throughout the lifespan in DS; (2) primary human cell cultures studies (Aim-2) that will investigate molecular mechanisms that link early AD pathology in DS with neuroinflammation and NGF metabolic dysfunction; and (3) biological fluids studies (Aim-3) that will analyze the expression of A?, tau, NGF-related and inflammatory markers in matched plasma and CSF samples from DS subjects across the lifespan. The proposed studies should help to identify early biomarkers and assist in the prediction of the onset and trajectory of AD dementia.
