Alzheimer’s disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies

Abstract

Alzheimer’s disease (AD) is the most common form of degenerative dementia and is characterized by progressive impairment in cognitive function during mid- to late-adult life. Brains from AD patients show several distinct neuropathological features, including extracellular β-amyloid-containing plaques, intracellular neurofibrillary tangles composed of abnormally phosphorylated τ, and degeneration of cholinergic neurons of the basal forebrain. In this review, we will present evidence implicating involvement of the basal forebrain cholinergic system in AD pathogenesis and its accompanying cognitive deficits. We will initially discuss recent results indicating a link between cholinergic mechanisms and the pathogenic events that characterize AD, notably amyloid-β peptides. Following this, animal models of dementia will be discussed in light of the relationship between basal forebrain cholinergic hypofunction and cognitive impairments in AD. Finally, past, present, and future treatment strategies aimed at alleviating the cognitive symptomatology of AD by improving basal forebrain cholinergic function will be addressed.

Introduction

Alzheimer’s disease (AD) is the most common form of degenerative dementia of the human central nervous system (for reviews, see Katzman, 1986, Francis et al., 1999, Perry and Hodges, 1999, Selkoe, 2001). Although recent evidence suggests that AD is a heterogeneous disorder comprising several different phenotypic and genotypic expressions, AD can be characterized clinically by a progressive impairment in cognitive function during mid- to late-adult life with the initial symptoms typically being certain forms of memory and language losses (Katzman, 1986, Hodges and Patterson, 1995, Selkoe, 1997, Lawrence and Sahakian, 1998, Bozeat et al., 2000, Marin et al., 2002). Brains from AD patients show several distinct neuropathological features, including extracellular amyloid-β (Aβ) peptide-containing plaques, intracellular neurofibrillary tangles of abnormally phosphorylated τ, astrocytic gliosis, reactive micoglia, and inflammation, as well as neuronal and synaptic losses (for reviews, see Geula, 1998, Lee et al., 2001b, McGeer and McGeer, 2001, Schubert et al., 2001, Selkoe, 2001). Although these neuropathological hallmarks of AD are particularly prominent in areas such as the parietal and temporal cortices, the hippocampus, the entorhinal cortex, and the amygdala, one of the earliest pathological events in AD is thought to be the degeneration of cholinergic neurons of the basal forebrain (Bowen et al., 1976, Davies and Maloney, 1976; Whitehouse et al., 1982a, Whitehouse et al., 1982b; Coyle et al., 1983, Pearson et al., 1983). Moreover, in addition to significant neuronal cell loss within this brain region, evidence implicating the basal forebrain cholinergic system in AD neuropathology comes from numerous studies demonstrating decreases in choline acetyltransferase (ChAT) activity (Bowen et al., 1976, Davies and Maloney, 1976; Perry et al., 1977a, Perry et al., 1977b, Perry et al., 1978; Bowen et al., 1979; Whitehouse et al., 1982a, Whitehouse et al., 1982b; Wilcock et al., 1982, Coyle et al., 1983, DeKosky et al., 1992, Lehericy et al., 1993), high affinity choline uptake (HACU) (Rylett et al., 1983), acetylcholine (ACh) release (Nilsson et al., 1986), and both nicotinic and muscarinic ACh receptor binding (Araujo et al., 1988, Whitehouse et al., 1988, Aubert et al., 1992, Nordberg et al., 1992, Perry et al., 1995) in post-mortem brain tissue of AD patients compared to non-pathological control brains. These basal forebrain cholinergic deficits positively correlate with cognitive impairments in AD (Perry et al., 1978, Collerton, 1986, DeKosky et al., 1992), as well as with non-cognitive behavioral disturbances (Minger et al., 2000).

Indirect support for basal forebrain cholinergic system involvement in the cognitive deficits accompanying AD also comes from considerable psychopharmacological evidence indicating that systemic administration of cholinergic receptor antagonists (e.g. scopolamine) interferes with the acquisition and performance of a variety of memory tasks in both rodents and non-human primates (Aigner and Mishkin, 1986, Aigner et al., 1991, Fibiger et al., 1991, Miller and Desimone, 1993). Moreover, together with studies demonstrating a correlation between ChAT activity and pre-mortem mental test scores (Perry et al., 1978, Wilcock et al., 1982), it was the finding that cholinergic blockade in normal humans has negative effects on cognition (Drachman and Leavitt, 1974, Drachman and Sahakian, 1980) that led to the development of the “cholinergic hypothesis of geriatric memory dysfunction” as it relates to AD (Bartus et al., 1982, Perry, 1988, Bartus, 2000). According to this hypothesis, the deterioration of cognitive function associated with AD dementia in the elderly is attributable to a decline in basal forebrain cholinergic neurotransmission. Support for this “cholinergic hypothesis” of cognitive impairment in AD comes from the fact that drugs that potentiate central cholinergic function have thus far proven to be the most effective forms of therapeutic treatment against the disease. However, such cholinomimetic replacement strategies have only met with limited success (Gauthier, 1999, Gauthier, 2002; Giacobini, 2000a, Giacobini, 2000b) in alleviating the cognitive deficits in AD, emphasizing the need for a better understanding of the way in which changes in central cholinergic systems are related to both AD symptomatology and disease progression.

This review will summarize evidence implicating basal forebrain cholinergic system involvement in AD pathogenesis and its accompanying cognitive deficits. Particular attention will be focused on recent results indicating a link between cholinergic mechanisms and the pathogenic events that characterize AD, notably in relation to Aβ peptides. Moreover, evidence indicative of impairments in trophic support for the basal forebrain cholinergic system in AD will be pointed out. The latest findings to emerge from animal models of dementia will be discussed in light of the new insights these studies provide into the relationship between basal forebrain cholinergic hypofunction and cognitive impairments in AD. Finally, we shall conclude by reviewing past, present, and future treatment strategies aimed at alleviating the cognitive symptomatology of AD by boosting basal forebrain cholinergic functions.