Fibrillar amyloid  beta-protein has been implicated in the pathogenesis of Alzheimer's disease because of its neurotoxicity and its ability to activate complement. Reactive microglia, astrocytes and complement (C') components are associated with senile plaques, the fibrillar,  beta-sheet assemblies of amyloid beta-peptide found predominantly in brain from individuals with AD. These indications of inflammatory events are not prevalent in the nonfibrillar 'diffuse' plaques often seen in age-matched control cases without dementia. Clinical studies over the past several years have correlated the use of anti-inflammatory drugs with a decrease in the incidence and progression of AD dementia and/or dysfunction, supporting a role for gliosis and inflammation in AD pathogenesis. C5a, a product of C' activation, is chemotactic for microglia.

    Thus, complement activation provides a specific mechanism for recruiting reactive glial cells to the site of the fibrillar amyloid beta-protein plaque, which could lead to inflammatory events, neuronal dysfunction and degeneration. With the use of truncated amyloid  beta-peptides, the region of amyloid  beta-protein limited by residues 4 and 11 has been identified as critical in the interaction between amyloid beta-protein and C1q, the recognition component of the classical complement pathway (CCP), which results in the activation of C'. Furthermore, substitution of an isoaspartic acid for aspartic acid at amyloid  beta-protein residue 7 resulted in the complete elimination of CCP-activating activity. A molecular model of this interaction has been generated that should be useful in the design of candidate therapeutic inhibitors of CCP activation by amyloid beta-protein.
 

    We report that human hNT cells display neuron-like calcium channel activation. Patch-clamp experiments show that exposure of hNT cells to the Alzheimer-related amyloid peptide beta AP(25-35) induces large and irreversible inward calcium currents at -80 mV in whole cell mode, with a linear current-voltage relationship. This behavior is suggestive of ionophore formation. An analogous peptide with scrambled sequence has no effect. These ionophore effects by the beta AP(25-35) peptide, the first report in a human cell-line, are very rapid effects. The currents are large and stable, and are blocked by Al3+ but not by Cd2+. Filtration removes a peptide aggregate from the amyloid peptide beta AP(25-35) solution and thereby abolishes the inward current. The residual soluble peptide has no effect. These data suggest that the initial step of the neurotoxic effect of beta AP(25-35) may be due to the insertion of the aggregated peptide into the cellular membrane as a Ca2+-carrying ionophore. The relevance of calcium-mediated cell death, especially in Alzheimer's disease, is discussed.
 

        Genetic evidence suggests a role for apolipoprotein E (apoE) in Alzheimer's disease (AD) amyloidogenesis. Here, amyloid-associated apoE from 32 AD patients was purified and characterized. We found that brain amyloid-associated apoE apparently exists not as free molecules but as complexes with polymers of the amyloid beta peptide (A beta). Brain A beta-apoE complexes were detected irrespective of the apoE genotype, and similar complexes could be mimicked in vitro. The fine structure of purified A beta-apoE complexes was fibrillar, and immunogold labeling revealed apoE immunoreactivity along the fibrils. Thus, we conclude that A beta-apoE complexes are principal components of AD-associated brain amyloid and that the data presented here support a role for apoE in the pathogenesis of AD.
 
 

    Transgenic FVB/N mice overexpressing human (Hu) or mouse (Mo) Alzheimer amyloid precursor protein (APP sub(695)) die early and develop a CNS disorder that includes neophobia and impaired spatial alternation, with diminished glucose utilization and astrogliosis mainly in the cerebrum. Age at onset of neophobia and age at death decrease with increasing levels of brain APP. HuAPP transgenes induce death much earlier than MoAPP transgenes expressed at similar levels. No extracellular amyloid was detected, indicating that some deleterious processes related to APP overexpression are dissociated from formation of amyloid. A similar clinical syndrome occurs spontaneously in similar to 20% of nontransgenic mice when they reach mid- to late-adult life, suggesting that APP overexpression may accelerate a naturally occurring age-related CNS disorder in FVB/N mice.
 

    The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta-42 peptide, peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid  beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels,  alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused   a highly significant increase in A beta-42 secretion in all mutant clones. Likewise, mutant but not  wild-type PS1 transgenic mice showed significant overproduction of A beta-42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta  generation. The extent of A beta-42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta-42  production, thus promoting cerebral beta-amyloidosis.