Faculty Bibliography

Anti-amyloid-beta immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-beta-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-beta active immunization on neurite trajectories and the pathological hallmarks of Alzheimer's disease in the human hippocampus. Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and eight age-matched non-demented controls. Analyses included neurite curvature ratio as a quantitative measure of neuritic abnormalities, amyloid and tau loads, and a quantitative characterization of plaque-associated neuritic dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively). The curvature ratio in non-immunized patients with Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). In immunized patients, however, the curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls. In the non-immunized patients, neurites close to dense-core plaques (within 50 microm) were more abnormal than those far from plaques (i.e. beyond 50 microm) (P < 0.0001). By contrast, in the immunized group neurites close to and far from the remaining dense-core plaques did not differ, and both were straighter compared to the non-immunized patients (P < 0.0001). Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-beta immunization on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 effectively improves a morphological measure of neurite abnormality in the hippocampus. This improvement is not just attributable to the decrease in plaque load, but also occurs within the halo of the remaining dense-core plaques. However, these remaining plaques still retain some of their toxic potential. Anti-amyloid-beta immunization might also ameliorate the hippocampal tau pathology through a decrease in tau phosphorylation. These data agree with preclinical animal studies and further demonstrate that human anti-amyloid-beta immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's disease.

In the developing spinal cord, motor neurons acquire columnar subtype identities that can be recognized by distinct profiles of homeodomain transcription factor expression. The mechanisms that direct the differentiation of motor neuron columnar subtype from an apparently uniform group of motor neuron progenitors remain poorly defined. In the chick embryo, the Mnx class homeodomain protein MNR2 is expressed selectively by motor neuron progenitors, and has been implicated in the specification of motor neuron fate. We show here that MNR2 expression persists in postmitotic motor neurons that populate the median motor column (MMC), whereas its expression is rapidly extinguished from lateral motor column (LMC) neurons and from preganglionic autonomic neurons of the Column of Terni (CT). The extinction of expression of MNR2, and the related Mnx protein HB9, from postmitotic motor neurons appears to be required for the generation of CT neurons but not for LMC generation. In addition, MNR2 and HB9 are likely to mediate the suppression of CT neuron generation that is induced by the LIM HD protein Lim3. Finally, MNR2 appears to regulate motor neuron identity by acting as a transcriptional repressor, providing further evidence for the key role of transcriptional repression in motor neuron specification.