From the Entorhinal Region via the Prosubiculum to the Dentate Fascia: Alzheimer Disease-Related Neurofibrillary Changes in the Temporal Allocortex

The pathological process underlying Alzheimer disease (AD) unfolds predominantly in the cerebral cortex with the gradual appearance and regional progression of abnormal tau. Intraneuronal tau pathology progresses from the temporal transentorhinal and entorhinal regions into neocortical fields/areas of the temporal allocortex. Here, based on 95 cases staged for AD-related neurofibrillary changes, we propose an ordered progression of abnormal tau in the temporal allocortex. Initially, abnormal tau was limited to distal dendritic segments followed by tau in cell bodies of projection neurons of the transentorhinal/entorhinal layer pre-α. Next, abnormal distal dendrites accumulated in the prosubiculum and extended into the CA1 stratum oriens and lacunosum. Subsequently, altered dendrites developed in the CA2/CA3 stratum oriens and stratum lacunosum-moleculare, combined with tau-positive thorny excrescences of CA3/CA4 mossy cells. Finally, granule cells of the dentate fascia became involved. Such a progression might recapitulate a sequence of transsynaptic spreading of abnormal tau from 1 projection neuron to the next: From pre-α cells to distal dendrites in the prosubiculum and CA1; then, from CA1 or prosubicular pyramids to CA2 principal cells and CA3/CA4 mossy cells; finally, from CA4 mossy cells to dentate granule cells. The lesions are additive: Those from the previous steps persist.

Ultrastructural Signs of Regenerative-Degenerative Processes in Long-Term Dentate Fascia Grafts

An ultrastructural investigation of embryonic (E20) dentate fascia grafts transplanted into an acute cavity in the somatosensory neocortex of adult rats revealed a continuous dynamic state of the tissue nine months postgrafting. The grafts consisted mainly of typical granular cells with some admixture of hippocampal pyramidal neurons and polymorph hilar cells with a normal, mature ultrastructure. Many features of the transplanted tissue suggested continuing development and growth. Dendritic branches with growth tips, axonal growth cones, synaptic boutons with growth vesicles, immature myelin sheaths and myelin-producing cells were observed. In contrast, ultrastructural signs of degeneration were present in some axons, and, less often, in dendrites. These processes, as well as some of the terminal synapses, contained various amounts of lysosomes and lipofuscine granules. In many such terminals the signs of degenerative change were combined with the presence of multiple mitochondria, polymorph vesicles and tubular reticulum, indicating simultaneous reparative processes. It is suggested that continuous recycling of neuronal processes occurs in longterm dentate grafts. This morphological instability nay depend on the paucity of synaptic targets within the dentate tissue transplanted with a minimal quantity of hippocampal pyramidal cells and on the limitation of the afferent input. However, the observed features of the grafted dentate tissue are not qualitatively different from those observed in normal dentate with its protracted development and active compensatory reorganization.