Cholinergic system during the progression of Alzheimer's disease: therapeutic implications

Abstract

Alzheimer's disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline acetyltransferase activity associated with cognitive decline. Delaying CBF neurodegeneration or minimizing its consequences is the mechanism of action for most currently available drug treatments for cognitive dysfunction in AD. Growing evidence suggests that imbalances in the expression of NGF, its precursor proNGF and the high (TrkA) and low (p75(NTR)) affinity NGF receptors are crucial factors underlying CBF dysfunction in AD. Drugs that maintain a homeostatic balance between TrkA and p75(NTR) may slow the onset of AD. A NGF gene therapy trial reduced cognitive decline and stimulated cholinergic fiber growth in humans with mild AD. Drugs treating the multiple pathologies and clinical symptoms in AD (e.g., M1 cholinoceptor and/or galaninergic drugs) should be considered for a more comprehensive treatment approach for cholinergic dysfunction.

Figure 1. Schematic diagrams show the shifting stoichiometric relationships of several gene products underlying cholinergic basal forebrain (CBF) survival during the progression of Alzheimer's disease (AD)

(A) The relationship between cortical levels of TrkA and proNGF and MMSE scores reveal that poorer performance on the MMSE is associated with decreased TrkA and increased proNGF protein levels in the cortex. (B) Shifts in the balance of NGF metabolism, NGF receptor and coreceptor expression, and tau isoform expression may contribute to the degeneration of CBF neurons in AD. MMSE: Mini Mental State Exam.