Evidences path(MESH:"Alzheimer Disease") to p(HGNC:CHRNA7)

In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006).

A stereological approach, in which specific, identified regions of cortex were excised as a by-product of therapeutic surgery, revealed an approximately 50% decrease in the number of alpha7-containing neurons in the temporal cortices of patients with AD, without overall loss in neuron number (Banerjee et al., 2000). In addition to loss of neurons, there are reports of reduced expression of specific nAChR subtypes, particularly of alpha4beta2 and alpha7 subunits, in many brain areas in AD.

It is noteworthy that a different pattern of changes in nAChRs is seen in non-neuronal cells; expression levels of alpha7 have been reported to be elevated in astrocytes of brains from patients with AD and in cultured astrocytes (Teaktong et al., 2003; Xiu et al., 2005; Yu et al., 2005). Likewise, studies comparing alpha7 expression in human AD brain and Swedish-mutant mice found enhanced alpha7 expression in astrocytes but decreased expression in neurons compared with controls (Xiao et al., 2006).

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.

Thus, in brains from patients with AD and in neurons responding to exogenously applied Abeta, there is a reduction in expression of nAChR subunits, especially alpha4, alpha7, beta4, and possibly alpha3. Although AD may also involve changes in expression of other ligand-gated ion channels— for example, the expression of NMDA receptors (Bi and Sze, 2002; Jacob et al., 2007), alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (Jacob et al., 2007), and beta3 GABA receptor subunits are all reduced (Mizukami et al., 1998)—there is abundant evidence of a loss of nAChR subunits in AD possibly caused by the actions of Abeta.

A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b)

Reduction of α7 AChRs in the CNS is linked with Alzheimer dis- ease, which has been shown to lead to neuronal loss [53,188–190].

AD brains show an upregulation of CHRNA7 (acr-14 homolog in humans) (84), where it may mediate the Ab-induced tau pathology (85).

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