Cerebral amyloidosis comprises a heterogeneous group of conformational disorders of different etiologies characterized by the deposition of fibrillar proteins in the brain parenchyma and blood vessel walls. The focus of my research has been the elucidation of common features of amyloid deposition diseases:

• Discovering genetic factors involved in hereditary forms of amyloidoses
• Characterizing the regulation of processing of amyloid precursor proteins
• Defining processes involved in the conversion of soluble protein to the insoluble, fibrillar form
• Identifying factors that target ubiquitously expressed proteins for deposition at restricted locations within particular tissues
  

Patients with Alzheimer's disease, Down's syndrome, and cerebral amyloid angiopathy (CAA) have amyloid deposits composed primarily of amyloid b-protein (Ab), a proteolytic fragment of b-amyloid precursor protein (bAPP). bAPP is an integral transmembrane glycoprotein whose proteolytic processing results in the generation and secretion of soluble bAPP amino-terminal peptides (sbAPP) as well as Ab. Ab and sbAPP are physiological ligands with reciprocal effects on neuronal integrity, survival and growth that may be regulated through control of the relative amounts of Ab and sbAPP in the vicinity of neurons. We are searching for proteins that bind Ab or bAPP, assuming that either disruption of normal binding or the formation of abnormal association with a specific protein may lead to fibrillogenesis. We have demonstrated that the PI/PTB domain of the adaptor proteins X11 and Fe65 bind to the YENPTY domain within the cytoplasmic domain of bAPP, participating in the regulation of bAPP processing. The therapeutic implications of this research lies in the fact that manipulation of the association of bAPP with a PI/PTB domain of X11 and/or Fe65 may affect the production of the amyloidotic Ab peptide and of the potentially neurotrophic sbAPP fragment.

We have demonstrated that hereditary form of CAA is linked to a mutation in the bAPP gene, resulting in an amino acid substitution in Ab. A variant of the cysteine proteinase inhibitor cystatin C is deposited in the cerebral vasculature in the Icelandic hereditary form of CAA. Specific amino acid substitutions in Ab and cystatin C may be the primary defects in these inherited disorders resulting in deposition primarily in the cerebral vasculature. We have generated lines of transgenic mice expressing either wild type or variant human cystatin C under control sequences of the human cystatin C gene or mouse smooth muscle a-actin promoter fragment SMP8. Histological analyses of brains of aged transgenic mice that died of natural causes did not reveal amyloid deposition in the vessel walls or in the neuropil. However, some of these mice had subarachnoid hemorrhages and others had intracerebral microhemorrhages. These data indicate that elevated brain and/or blood levels of cystatin C can cause hemorrhagic strokes. In the brain of aged individuals and Alzheimer’s disease patients, cystatin C codeposits with Ab. It has been suggested that the risk of cerebral hemorrhage increases when high levels of cystatin C are present in cerebrovascular Ab deposits. We have demonstrated high affinity binding between cystatin C and Ab suggesting that cystatin C binding to Ab may cause local accumulation of the protease inhibitor, contributing to hemorrhages.