Evidences path(MESH:"Alzheimer Disease") to p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")

Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432).

However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374).

It is noteworthy that nAChR expression by astrocytes in brains afflicted with AD is increased (463, 518), and astrocytes in general have been reported to be more plentiful in the hippocampus of some rat strains with age (35, 284).

AD also involves loss of neurons, beginning in the entorhinal cortex and later spreading to the neocortex (Braak et al., 2006); early in the disease, nicotinic acetylcholine receptors (nAChRs) are lost (Kadir et al., 2006).

Several lines of evidence point to a link between brain nAChRs and the development of AD. Biochemical analysis of brains of patients with AD reveals deficits in nAChRs, an increase in butyrylcholinesterase, reduction in ACh, and attenuated activity of cholinergic synthetic [choline acetyltransferase (ChAT)] and inactivating (AChE) enzymes (Bartus et al., 1982; Francis et al., 1999).Butyrylcholinesterase and AChE help terminate ACh signaling by hydrolyzing the transmitter, thereby inactivating it.

Thus, although other mechanisms are also involved in the development of AD, there is abundant evidence that defects in cholinergic synaptic transmission and, in particular, nAChR-mediated signaling plays a major role in the disease and are hence the subject of attempts to generate new routes to therapy.

It is clear that AD involves loss of cholinergic neurons in the brain as well as an overall reduction in nAChRs, and it seems that different subunits are differentially up- or down-regulated in AD in different brain regions and different cell types.

Thus, predominantly alpha4 and alpha7 subunits, and to a lesser extent alpha3 subunits, are lost in AD, although there are tissue-specific differences to this pattern, such as the upregulation of nAChRs on astrocytes.

The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine (ACh) exerts its physiological functions by activating either ionotropic nicotinic ACh receptors (nAChRs) or metabotropic muscarinic ACh receptors (mAChRs). It has been reported that in AD brains there are (1) reduced choline acetyltransferase levels accompanied by decreased ACh synthesis; (2) significant loss of cholinergic neurons; (3) reduction in the numbers of postsynaptic neurons accessible to ACh; (4) cholinergic neuronal and axonal abnormalities; and (5) reduction in nAChR levels

Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127.

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