The loss of cholinergic markers during Alzheimer's disease and aging has led to the cholinergic hypothesis of memory deficits

Cholinergic functions, which are quantitatively minor among other brain neurotransmitters, are studied intensively because of this hypothesis [25]. In general, aging changes in neurotransmitters and receptors are selective in rodents and neurologically normal humans. Many changes are not consistent even in the same species, for example, whether cholinergic forebrain neurons atrophy or hypertrophy at different times during aging [2]. The largest age changes, however, are relatively modest by comparison with the major (>90%) loss of basal ganglia DA during PD (see Chap. 45) and the variable (25 to 90%) loss of choline acetyltransferase (ChAT) and other cholinergic markers during AD (see Chap. 46) [23,25]. A key point is that receptor affinity as measured by ligand binding does not change markedly with aging.

Age-related changes in synaptic chemistry and physiology are robust phenomena in a few neural systems, in which the scheme from gene expression to synaptic functions is partly mapped for aging changes [23–26]. Hippocampus (HC), striatum (ST) and cerebral cortex (CTX) of aging rodents show different features of cholinergic aging, in conjunction with changes in anatomy and other neurotransmitters, particularly DA (Table 30-4).

Table 30-4

Age-Related Changes in Mammalian Brain Neurotransmitters, Receptors and Responses^a.

The ST has some of the most consistent neurochemical aging changes in mammals. Progressive declines of D2R are shown by ligand binding in mice, rats, rabbits and human brain and by positron emission tomographic (PET) imaging (see Chap. 54) in humans [25,26]. These declines can be detected during midlife, when they are not confounded by age-related pathology, and appear to be progressive, reaching net decreases of 20 to 40% by the life span. DA loss is smaller and more irregular in rodents than in humans but far less in any case during aging than in PD [2,23]. The loss of D2R is paralleled by a decrease of D2R mRNA in aging rodents [15]. These changes are attributed to two causes: a 20% loss of intrinsic ST cholinergic neurons, a major location of the D2R, and a slowed synthesis of the D2R. Despite their 10 to 50% decrease, D2R show no age-related dysfunctions in the sensitivity of DA release to haloperidol in perfused slices. Impairments in DA-activated adenylyl cyclase (see Chap. 12) are reported consistently, but there is no consensus on age changes in the D1R.

Cholinergic controls over transmitter release show marked but selective impairments of DA and acetylcholine (ACh) release in ST and of ACh release in HC and CTX of aging rats. The details of cholinergic receptor types are discussed in Chapter 11. Most reports agree on sizable age-related decreases in nicotinic and muscarinic M₂-binding sites in HC, CTX and ST [23,24,27]. Although no age changes are found in mRNAs for some M₁, M₃ and M₄ receptors in ST or in other brain regions, the mRNA for the M₂R has not been resolved for possible effects of age. Major impairments were identified with the M₂ control of DA release. Muscarinic control of ACh release, presumably via M₂ autoreceptors, had a different pattern, with no age change in ST but marked impairments in HC and neocortex [25] (Fig. 30-2). These regional differences imply that the M₂ sites lost with aging in ST are not on local cholinergic neurons.

Figure 30-2

Acetylcholine (ACh) release by brain slices at increasing concentrations of the muscarinic agonist AF-DX 116 relative to controls (100%). Slices were taken from the indicated brain regions of male rats at the indicated ages. In cortex and hippocampus, (more...)

Postsynaptic receptor defects are implicated in several aging changes in HC, CTX and ST [25]. Unit recordings show a repeatable decrease in sensitivity of HC neurons to ACh in vivo and in vitro. The low-affinity GTPase activity stimulated by carbachol or oxotremorine was impaired by ≥30% in HC and ST. Of the many G proteins (described in Chap. 20), only the GTP-binding subunits G_αi and G_αo have been assayed; these showed no age change in ST or HC. In ST, in contrast to the reduced sensitivity to muscarinic agonists, the calcium ionophore A23087 and the signal transducer inositol 1,4,5-trisphosphate (IP₃) (Chap. 21) showed no age impairment in enhancing K⁺-stimulated DA release. Reports of age changes in ACh-stimulated phosphoinositide metabolism (see Chap. 21) are not consistent. An impairment of Ca²⁺ regulation is implied at the ligand—muscarinic receptor interface.

Moreover, there are age-related changes of intraneuronal Ca²⁺ metabolism in HC and elsewhere. For example, Ca²⁺-dependent, K⁺-mediated afterhyperpolarization increases by 50% with age, as measured in HC slices [7,18]. Changes in corticosteroids and other hormones may contribute to disturbances in local or even systemic Ca²⁺ and inorganic phosphate (P_i) homeostasis during normal aging and AD [7,28]. Renal lesions and elevations of parathyroid and calcitonin hormones are common in aging rats [1] and may interact with brain aging. Normal intracellular Ca²⁺ regulation is detailed in Chapter 23.

Nerve growth factor (NGF) treatment partially reversed the perikaryal atrophy in cholinergic projections to the HC in aging rats and improved learning performance [2,29]. ChAT in the rat ST retains responsiveness to NGF throughout the life span and may even become more sensitive [2]. In view of the lack of change in NGF mRNA in aging rats or in AD, aging in these systems may not be attributed to deficits of NGF. There is some evidence of age-related diminution of the norepinephrine, serotonin, glutamate and GABA systems; as found for DA and cholinergic systems, these changes show regional differences [25,26].