Alzheimer  >   15. The Origin of Alzheimer's Disease

It has been known for decades that Alzheimer's disease (AD) begins in the entorhinal cortex (EC). Recently, experiments further identified the lateral entorhinal cortex (LEC) as the original site (Khan et al., 2014). LEC is functionally distinct from the adjacent medial entorhinal cortex (MEC) which processes space information (Witter et al., 2017) while LEC plays a central role in cognition (Bota et al., 2015), which requires long-range communication among widely separated brain areas, even between two cerebral hemispheres. Therefore, the finding lends another support to the mechanism of long-range synchronization and BDNF Cascade Hypothesis for AD.

Anatomically, LEC has direct projections to the entire cortical mantle in rats (Swanson and Köhler, 1986). Connectome analysis also reveals that LEC has the most cortical association connections of all (Bota et al., 2015). Thus, LEC could be heavily engaged in long-range synchronization which is regulated by microtubules and Tau protein at the axon initial segment (AIS). Intriguingly, by studying the expression profile of Tau proteins in different brain regions, Hu et al. (2017) found that the expression level of 4R-Tau was the highest in EC. According to the model presented in Chapter 9, 4R-Tau can cause longer duration of microtubule dissociation from the AIS membrane than 3R-Tau, thereby increasing the long-range coupling with other brain areas.

Like other cortical areas, LEC contains three type of GABAergic interneurons: parvalbumin (PV)-positive, somatostatin (SOM or SST)-positive and cholecystokinin (CCK)-positive. CCK cells are also called 5HT3R interneurons because they express 5-HT3 receptors. The PV cells oscillate at the gamma band (30-80 Hz) which is critical for cognition. They are also referred to as fast-spiking (FS) interneurons. SOM cells fire at 10-30 Hz with low threshold, thus also called low-threshold-spiking (LTS) interneurons (Mancilla et al., 2007). During theta oscillations, CCK cells fire at 8.8 ± 3.3 Hz on the ascending phase of theta waves (Klausberger et al., 2005).

In a knock-in mouse model of AD (AppNL-F/NL-F), the PV cells of LEC were found to be hypoactive, resulting in hyperexcitability and excitotoxicity in the postsynaptic pyramidal neurons (Petrache et al., 2019). The cause of hypoactivity in PV cells is not clear. In the cortex, PV cells are commonly regulated by other GABAergic interneurons, such as the SOM cells (Yavorska and Wehr, 2016). However, evidence for the involvement of SOM cells in AD is scarce. Furthermore, the cholinergic inputs from the medial septum to LEC target mainly CCK (5HT3R) cells (Desikan et al., 2018). Therefore, it is reasonable to assume that the hypoactivity of PV cells in LEC is caused by hyperactive CCK cells (Figure 15-1). Hence, AD could originate from hyperexcitability of CCK cells and pyramidal neurons in LEC.


Figure 15-1. The proposed microcircuit in lateral entorhinal cortex. Tau-mediated hyperexcitability could occur in CCK cells and pyramidal neurons. ACh: cholinergic neuron; CCK: cholecystokinin-positive GABAergic interneuron; PV: parvalbumin-positive GABAergic interneuron.

In line with this hypothesis, selective activation of CCK cells has been shown to enhance memory and cognition (Whissell et al., 2019). Higher cerebrospinal fluid (CSF) CCK levels correlate with decreased likelihood of having mild cognitive impairment or AD. CSF CCK is also strongly related to higher CSF total tau and phosphorylated Tau, but not Aβ1-42, suggesting that CCK may increase for compensatory protection as AD pathology progresses (Plagman et al., 2019). This protective response may account for, at least in part, the less dramatic reduction of CCK than SOM in the AD brain (Mazurek and Beal, 1991).


Author: Frank Lee
First published: August 13, 2019