An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death.

The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.

Sequestration of malaria-parasite-infected erythrocytes in the microvasculature of organs is thought to be a significant cause of pathology. Cerebral malaria (CM) is a major complication of Plasmodium falciparum infections, and PfEMP1-mediated sequestration of infected red blood cells has been considered to be the major feature leading to CM-related pathology. We report a system for the real-time in vivo imaging of sequestration using transgenic luciferase-expressing parasites of the rodent malaria parasite Plasmodium berghei. These studies revealed that: (i) as expected, lung tissue is a major site, but, unexpectedly, adipose tissue contributes significantly to sequestration, and (ii) the class II scavenger-receptor CD36 to which PfEMP1 can bind is also the major receptor for P. berghei sequestration, indicating a role for alternative parasite ligands, because orthologues of PfEMP1 are absent from rodent malaria parasites, and, importantly, (iii) cerebral complications still develop in the absence of CD36-mediated sequestration, dissociating parasite sequestration from CM-associated pathology. Realtime in vivo imaging of parasitic processes may be used to evaluate the molecular basis of pathology and develop strategies to prevent pathology.imaging ͉ Plasmodium ͉ P. berghei ͉ luciferase ͉ real-time in vivo imaging I nfected red blood cells (irbc) of many species of malaria parasites adhere to the endothelial cells of the microvasculature of numerous deep tissues (1, 2). Termed sequestration, this characteristic may facilitate parasite multiplication, avoiding removal of the irbc by the spleen (3, 4). In some parasite-host combinations, the process of sequestration is associated with pathogenesis, for example, Plasmodium falciparum in humans (1, 2, 5) and Plasmodium berghei in certain mouse strains (6, 7). Cerebral malaria (CM) is a major complication of P. falciparum infections, and the sequestration of irbc has been considered to be the major feature leading to CM-related pathology. Sequestration may lead to vascular obstruction, local endothelial cell activation, and the release of proinflammatory cytokines, resulting in damage to adjacent tissues (2, 7, 8). In P. falciparum, the class II scavenger receptor CD36 is a major endothelial receptor. CD36 is involved in not only the adherence of irbc (1, 9, 10) through specific domains of the surface variant antigen PfEMP-1 but also in the modulation of innate and adaptive immune responses (11,12). To date, most investigations of the dynamics of irbc-receptor interactions rely on in vitro observations with cultured cells and immobilized receptors (2). Despite the increase in knowledge of the molecules involved in the binding of irbc to endothelial cells, the specific interactions that lead to pathology have yet to be established. Infection with P. berghei in laboratory rodents is a well established model for the investigation of associations among CM, proinflammatory cytokines, and endothelial receptors involved in the sequestration of irbc, leukocytes, and platelet...