Cholinergic basal forebrain circuit degeneration in Alzheimer's disease

Alzheimer's disease is characterized by loss of synapses and neurons in specific areas of the brain, leading to loss of learning, memory and cognitive function. Among the most vulnerable neurons in Alzheimer's disease are basal forebrain cholinergic neurons. Degeneration of cholinergic projections to cortex and hippocampus is responsible for learning and memory deficits. Basal forebrain cholinergic neurons rely on two target‐derived neurotrophic factors, nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF), to maintain survival, differentiation, connectivity and function. NGF and BDNF are dysregulated in Alzheimer's disease by very different mechanisms. NGF is found in the brain in its precursor form, proNGF, which accumulates in Alzheimer's disease and becomes toxic to basal forebrain cholinergic neurons. BDNF, on the other hand, is decreased in Alzheimer's disease at the transcriptional level, causing cholinergic dysfunction and synapse loss. The molecular pathways for BDNF down‐regulation have been partially elucidated, and recent work demonstrates that lifestyle changes can raise BDNF levels and rescue age‐related cognitive impairment. Nevertheless, a full understanding of the causes and mechanisms of basal forebrain cholinergic neuron degeneration in Alzheimer's disease remains a challenge.