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.
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.
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.