Enlargement of early endosomes and traffic jam in basal forebrain cholinergic neurons in Alzheimer's disease.

While a handful of neurotransmitter systems including cholinergic, norepinephrinergic, and serotonergic undergo significant degeneration in Alzheimer's disease, the cholinergic system has been the prime target for research and therapy. The cholinergic system in the basal forebrain is strategically located to impose significant modulatory effects on vast cortical and subcortical regions of the brain. Numerous studies have established a strong link between neurotrophin signaling and basal forebrain cholinergic neuron degeneration in several neurodegenerative disorders. Evidence presented during the last few years points to the effects of endosomal pathology and primarily unidirectional traffic jam. Hence, formulating new therapies, e.g., to reduce local production of β C-terminal fragments and preventing changes in endosomal morphology have become attractive potential therapeutic strategies to restore cholinergic neurons and their neuromodulatory function. While it is not expected that restoring the cholinergic system function will fully mitigate cognitive dysfunction in Alzheimer's disease, pivotal aspects of cognition including attention-deficit during the prodromal stages might well be at disposal for corrective measures.