More Than Just A Neuron: A New Trick From An Old Dog

The term neuron refers to an electrically excitable cell specialized for the reception, processing, and transmission of information (electrochemical signals) throughout the nervous system and the rest of the body. Neurons are the principal structural and functional blocks of the central and peripheral nervous system empowering fast, accurate, and coordinated information exchange between various body parts and organs to warrant their coherent and coordinated functioning within an organism, which is critical for adaptation and survival. It is the highly complex and coordinated interaction of over 100 billion neurons that controls every facet of human life and behavior.

The vast majority of neurons are structurally and functionally independent but tightly associated in complex networks via synaptic connections. Most of them are also polarised to receive information on their short and dense processes called dendrites, and after processing, to pass it along their axons onto downstream effectors. There are numerous exceptions to the polarization rule, with some neurons propagating information in both forward and backward directions. Others are known to contact and release chemicals from their dendrites directly into the bloodstream and, hence, function as neuroendocrine cells. These cells are evolutionarily very old and specialized for governing slow metabolic and housekeeping functions and typically lack a means for fast and long-range signal transmission.

Another intriguing exception from the traditional notion of neurons as polarized information processing modules has emerged recently in the discovery of previously unrecognized homeostatic functions of unique, so-called cholinergic forebrain neurons, a specialist nerve group known to be compromised by normal aging and especially Alzheimer’s disease. These are a relatively small population of neurons localized within a chain of nuclei at the base of the forebrain, which regulate the state and the activity of the brain by releasing neurotransmitter acetylcholine in the cortex and hippocampus. Acetylcholine is a potent modulator of neuronal function and activity.

An intriguing feature of cholinergic neurons, which emerged recently, is that in addition to an acetylcholine-mediated neuromodulator role, they are capable of sequestering and removing the amyloid beta peptide from their innervation fields. This process is of major significance for healthy aging and especially Alzheimer’s disease as amyloid beta peptide is well known as the primary causative of this condition.

Exposure of cholinergic neurons to amyloid beta was shown to facilitate its rapid uptake followed by intracellular transport and breakdown in specialized degradation compartments known as lysosomes. Through such an intricate mechanism, cholinergic projections via a dense system of innervations “drains” excessive amyloid beta from the brain. This process is mediated via the specialized p75 neurotrophin receptor. The uptake and breakage of amyloid beta by cholinergic neurons, thus assigns these specialist neurons a novel, homeostatic functionality in amyloid beta clearance, a mechanism suspected to play a critical role not only in controlling the physiological levels of this peptide but also in brain aging and pathobiology of Alzheimer’s disease.

In-depth research and interpretation of this novel functionality of one of the largest modulator brain systems is hoped to elucidate fundamentally new homeostatic processes, to shed light on the brain physiology and neurodegenerative disease mechanisms related to excessive depositions of amyloid beta.

FIGURE 1: (A) Schematic of basal forebrain cholinergic system of the human brain. Cholinergic neurons via their ascending projections release acetylcholine (red arrows) to modulate cortical functions via different cholinergic receptor mediated processes. The same system of axons internalizes and removes from the cortex amyloid beta and other neurotrophins (blue arrows). 
(B) Intracellular journey of amyloid beta after internalization by cholinergic neurons. Note that part of this peptide is sorted to lysosomes for degradation (grey vesicles). Image taken from Ovsepian and Herms: Cholinergic neurons-keeping check on amyloid β in the cerebral cortex. Front Cell Neurosci. 2013 Dec 11;7:252.

These findings are described in the article entitled Drain of the brain: Low-affinity p75 neurotrophin receptor affords a molecular sink for clearance of cortical amyloid β by the cholinergic modulator system, recently published in the journal Neurobiology of AgingThis work was conducted by Saak V. Ovsepian and Jochen Herms from the German Center for Neurodegenerative Diseases.


  1. Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission. Ovsepian SV, O’Leary VB, Zaborszky L. Neuroscientist. 2016 Jun;22(3):238-51.
  2. Drain of the brain: low-affinity p75 neurotrophin receptor affords a molecular sink for clearance of cortical amyloid β by the cholinergic modulator system. Ovsepian SV, Herms J. Neurobiol Aging. 2013 Nov;34 (11):2517-24.