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Commentary: Monkey Brain Injections
by Brian Cummings
July 18, 1998 Bruce Yankner took time out from his talk on Down's syndrome (abstract 7)
to discuss his recent injection studies in young versus aged rhesus
monkeys, published in the July issue of "Nature Medicine." His key
findings were that injections of fibrillar Abeta at a "plaque equivalent
dose" resulted in cell loss, the proliferation of microglia and tau
hyper-phosphorylation in aged animals, but not young ones. These
findings are in contrast to earlier studies by Podlisny and Selkoe
(where "adult" but not "aged" monkeys were used).
Yankner showed an interesting example of immunocytochemical staining for
Abeta revealing an "injected plaque" near a natural plaque in an aged
monkey. The injected Abeta was more lightly stained and diffuse than
the natural plaque, and was oblong in shape, as if oriented along the
needle tract. Without the natural plaque present for comparison, one
would have assumed the artificial plaque was real based on morphology.
Yankner used several antibodies to hyper-phosphorylated tau, including
Ser-262, PHF-1 and AT8 to demonstrate dystrophic neurites in response
to the injection. He indicated that Ser-262 yielded the strongest
staining, with PHF-1 next and weak staining by AT8. This reaction was
not seen in the brains of young rhesus monkeys. In the brief time
allotted, he was unable to show slides of vehicle injections in neither
aged monkeys nor Abeta injections in young monkeys for the audience to
evaluate. Given Selkoe's observations that the neuropil response to
vehicle injections was indistinguishable from Abeta injections and
Bishop et al's poster (abstract 535) which shows that there is neuronal
damage and loss surrounding saline control injections into rat brain
this is an important question. The curious will have to examine
Yankner's Nature Medicine paper for the details.
Yankner favors the position that extracellular Abeta is the bad guy
compared to intracellular Abeta, pointing out that the intracellular
Abeta 'load' is "minuscule" compared to the extracellular 'load'. Thus,
the toxic effects of extracellular Abeta are probably more important.
He hypothesizes that intracellular Abeta from a cell which lyses could
lead to a seeding process which accumulates extracellular Abeta,
propagating the problem.