Mapping of amyloidogenic peptides induced genotoxicity in relevance to neuronal cell death

Amyloidogenic peptides play an important role in neurodegeneration. Recently, there
are reports on the nuclear localization of amyloids and proposed to have implications
to DNA damage and neuronal apoptosis. The mechanism of amyloidogenic peptides
induced neuronal cell death is still not clear. Our main questions are, (i) mapping of
amyloidogenic peptides induced genotoxicity; (ii) A(1-42) induced genomic
instability in aged rabbits and (iii) to study anti-amyloidogenic properties of
indigenous plants. To achieve these objectives we have employed agarose gel, Tm,
EtBr binding, DNase I sensitivity assay, CD, MRI and TEM techniques. The results
are summarized as follows: (i) A fragments (1-11, 1-28, 1-40 and 1-42) nick scDNA
and causes the open circular and linear forms. The Mg2+ ion enhanced the nicking
activity of A fragments (1-11, 1-28, 1-40 and 1-42). The modification of histidine of
A(1-11) abolished the DNA nicking activity. The DNA instability by studying Tm
and EtBr binding revealed that DNA became unstable in presence of different
fragments of A. (ii) The aged (4 yr) New Zealand rabbits were intracisternally
injected with A(1-42) and DNA analyzed from aged rabbits for stability showed that
DNA is damaged in FC and H; where as in M, DNA is in condensed state. The DNA
conformation study evidenced the presence of C,  and - type DNA conformations
in FC, H and M of A(1-42) injected (25 days) rabbit brain regions respectively. MRI
studies showed no significant changes in brain structures between control and A(1-
42) injected aged rabbit brain regions. MRI scanning before and after 45 days of A
injection found significant reduction in the thickness of hippocampus, temporal lope,
frontal lobe, and midbrain and an increase in lateral ventricle volume. Additionally,
the aqueous leaf extracts of C. crista and C .asiatica could not prevent the DNA
nicking activity of A(1-42). The CG and VG induced modified conformations in
A(1-11), A(1-28) and A(25-35). The aqueous extracts of C. crista and C. asiatica
showed anti-oxidant and anti-inflammatory activities. The C. crista showed antiamyloidogenic
properties.