Several mutations in the amyloid precursor protein (APP) gene have been found to associate with pathologic deposition of the beta-amyloid peptide (Abeta) in neuritic plaques or in the walls of cerebral vessels. We report a mutation at a novel site in APP in a three-generation Iowa family with autosomal dominant dementia beginning in the sixth or seventh decade of life. The proband and an affected brother had progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Neuropathological examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of Abeta40 in plaques. The affected brothers shared a missense mutation in APP, resulting in substitution of asparagine for aspartic acid at position 694. This site corresponds to residue 23 of Abeta, thus differing from familial Alzheimer's disease mutations, which occur outside the Abeta sequence. Restriction enzyme analysis of DNA from 94 unrelated patients with sporadic cerebral amyloid angiopathy-related hemorrhage found no other instances of this mutation. These results suggest a novel site within Abeta that may promote its deposition and toxicity.

Although thrombolysis with tissue plasminogen activator (tPA) is a stroke therapy approved by the US Food and Drug Administration, its efficacy may be limited by neurotoxic side effects. Recently, proteolytic damage involving matrix metalloproteinases (MMPs) have been implicated. In experimental embolic stroke models, MMP inhibitors decreased cerebral hemorrhage and injury after treatment with tPA. MMPs comprise a family of zinc endopeptidases that can modify several components of the extracellular matrix. In particular, the gelatinases MMP-2 and MMP-9 can degrade neurovascular matrix integrity. MMP-9 promotes neuronal death by disrupting cell-matrix interactions, and MMP-9 knockout mice have reduced blood-brain barrier leakage and infarction after cerebral ischemia. Hence it is possible that tPA upregulates MMPs in the brain, and that subsequent matrix degradation causes brain injury. Here we show that tPA upregulates MMP-9 in cell culture and in vivo. MMP-9 levels were lower in tPA knockouts compared with wild-type mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP-9 was upregulated when recombinant tPA was added. RNA interference (RNAi) suggested that this response was mediated by the low-density lipoprotein receptor-related protein (LRP), which avidly binds tPA and possesses signaling properties. Targeting the tPA-LRP signaling pathway in brain may offer new approaches for decreasing neurotoxicity and improving stroke therapy.

Background: APOE genotype effects on A␤ accumulation were determined using new EFAD transgenic mice. Results: In E4FAD mice, compact plaques are greater, total apoE4 is lower, less apoE4 is lipoprotein-associated, and oligomeric A␤ is higher compared with E2FAD/E3FAD, while intraneuronal A␤ is unaffected. Conclusion: APOE4 uniquely effects A␤ accumulation. Significance: These data provide a basis for APOE-induced AD risk.

To explore the clinical effects of inflammation associated with vascular deposits of the amyloid beta peptide (A beta), we analyzed 42 consecutive patients with pathologically diagnosed cerebral amyloid angiopathy (CAA) for evidence of an inflammatory response. Inflammation with giant-cell reaction surrounding amyloid-laden vessels was identified in 7 of the 42 cases. The clinical symptoms in each of the seven were subacute cognitive decline or seizure rather than hemorrhagic stroke, the primary clinical presentation in 33 of 35 patients with noninflammatory CAA (p < 0.001). Inflammatory CAA also was associated with radiographic white matter abnormalities, significantly younger age at presentation, and a marked overrepresentation of the apolipoprotein E epsilon 4/epsilon 4 genotype (71% vs 4%, p < 0.001). Of the six inflammatory CAA patients with available follow-up information, five demonstrated clinical and radiographic improvement after immunosuppressive treatment. The syndrome of CAA-related perivascular inflammation appears to represent a subset of CAA with clinically distinct symptoms that may respond to immunosuppressive treatment. These data add to evidence that inflammation against A beta can cause vascular dysfunction, a potential mechanism for the toxic response recently observed in clinical trials of A beta immunization.