Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer's disease

Abstract

All neurons are not created equal. Certain cell populations in specific brain regions are more susceptible to age-related changes that initiate regional and system-level dysfunction. In this respect, neurons in layer II of the entorhinal cortex are selectively vulnerable in aging and Alzheimer's disease (AD). This paper will cover several hypotheses that attempt to account for age-related alterations among this cell population. We consider whether specific developmental, anatomical, or biochemical features of neurons in layer II of the entorhinal cortex contribute to their particular sensitivity to aging and AD. The entorhinal cortex is a functionally heterogeneous environment, and we will also review data suggesting that, within the entorhinal cortex, there is subregional specificity for molecular alterations that may initiate cognitive decline. Taken together, the existing data point to a regional cascade in which entorhinal cortical alterations directly contribute to downstream changes in its primary afferent region, the hippocampus.

Figure 1

Morphological and connectional heterogeneity among principal neurons in layer II of the medial and lateral entorhinal areas. (a) In the medial entorhinal cortex (MEC), stellate cells are the most numerous class of excitatory neuron in layer II. However, pyramidal neurons and horizontal tripolar cells also reside in layer II and send afferents to the hippocampus via the perforant pathway. Layer II neurons in the MEC receive input from the postrhinal cortex (POR), and to a lesser extent from the perirhinal cortex (PER), and also from the subiculum/parasubiculum (Sub/Parasub) of the hippocampus. Whether these inputs preferentially contact a particular morphological class of layer II neuron remains to be determined. (b) In the lateral entorhinal cortex (LEC), fan cells are the most frequently observed, but pyramidal and multiform neurons also contribute axonal input to the perforant pathway. Layer II neurons of the LEC receive strong input from the PER, weaker input from the POR, as well as from the Sub/Parasub region of the hippocampus proper. All connectivity information is based on a review by Van Strien and colleagues [14].

Figure 2

Microenvironmental changes interact with intrinsic cellular alterations to promote the selective vulnerability of entorhinal layer II neurons in aging and AD. Neurons located further away from plaques are likely to maintain a greater degree of structural and functional integrity in AD, while neurons situated close to plaques and in the vicinity of the vasculature are exposed to elevated levels of inflammatory cytokines such as tumor-necrosis factor-alpha (TNF alpha) and monocyte chemoattractant protein 1 (MCP1). Proinflammatory alterations in the local microenvironment, together with intrinsic changes in neuronal reelin (Reln), brain-derived neurotrophic factor (BDNF), and tissue inhibitor of metalloproteinase 3 (TIMP3) expression, could potentially impair synaptic function. This impairment would alter signal propagation both locally, through reductions in NMDA NR1 subunit and muscarinic acetylcholine receptor M1 (mAChR1) expression, and downstream in the hippocampus, through reductions in synaptophysin expression in the terminal fields for layer II entorhinal neurons.