Neuropathological and amyloid peptide differences between DS and familial AD with duplications and missense mutations in APP gene

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of amyloid plaques mainly constituted of extracellular amyloid beta peptides (Abeta) deposits in brain parenchyma and intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau protein. Additionally Abeta can be found deposited in blood vessel walls as cerebral amyloid angiopathy (CAA), a major cause of intracerebral hemorrhage. While the presence of amyloid plaques in postmortem brains is common to all AD cases including sporadic, familial and Down syndrome (DS, trisomy of chromosome 21, with overdose of the Amyloid Precursor Protein (APP) gene on Hsa21), CAA is a more prominent phenotype in familial cases with either APP duplication or certain (but not all) point mutations. The nature and mechanisms underlying these pathological and clinical differences between APP causes of AD remain unclear. We propose a unique study specifically focusing on rare and poorly studied patient groups focusing on rare and poorly studied, but potentially very informative patient groups - those with APP mutations and duplications and DS - to elucidate differences that may provide important clues for treatment. We plan to investigate the diversity of clinical and neuropathological phenotypes associated with the diversity of alterations in the APP gene by studying endo-lysosomal alterations and Abeta species neuropathological differences in human cases, novel mouse models, and in several cell types derived from iPSC lines reproducing various diseases to unravel pathophysiological mechanisms involved in specific Abeta deposition.