Elevated ferritin expression in microglia and extracellular amyloid-β deposition are associated with reduced neurofibrillary degeneration in human isocortex, but not allocortex.

BackgroundPrior work in preclinical late-onset Alzheimer's disease (LOAD) focused on neuritic plaque development suggested that intracellular ferritin expression in microglia and extracellular deposition of amyloid-β (Aβ) are innate neuroprotective mechanisms geared specifically towards limiting aging-dependent increases in intracerebral free iron which likely contribute to development of neurofibrillary degeneration (NFD).ObjectiveImprove understanding of LOAD pathogenesis.MethodsImmunohistochemical comparison of the extent of NFD with the intensity of ferritin expression and Aβ deposition in three brain regions, including temporal lobe (entorhinal cortex, hippocampus), frontal, and occipital cortex in 34 non-demented human subjects at Braak stages II-III.ResultsFerritin-positive microglia are present with similar quantity and intensity in the allo- and isocortices of every individual in the cohort. Extracellular Aβ deposition in the isocortex is observed before substantial NFD develops, but in the allocortex (temporal lobe) there are no Aβ deposits in 50% of subjects despite extensive NFD. Cytoskeletal lesions in the allocortex consist of atrophic grid cells, abundant pretangles, neuropil threads, neurofibrillary tangles, and neuritic plaques; isocortical sites show either no NFD at all or only minimal NFD presenting as solitary pretangles or tangles, neuropil threads, or droplet degeneration spheres from ferroptotic neurons. Presence of degenerating grid neurons in entorhinal cortex coincides with microglial apoptosis.ConclusionsNeuroprotection via ferritin expression and Aβ deposition is more effective in the isocortex than in allocortex. Findings support the hypothesis that degeneration or death of neuroprotective microglia promotes neuronal degeneration.