Reduction of cortical TrkA but not p75^NTR protein in early‐stage Alzheimer's disease

Abstract

Degeneration of cholinergic nucleus basalis (NB) cortical projection neurons is associated with cognitive decline in late-stage Alzheimer's disease (AD). NB neuron survival is dependent on coexpression of the nerve growth factor (NGF) receptors p75(NTR) and TrkA, which bind NGF in cortical projection sites. We have shown previously a significant reduction of NB perikarya expressing p75(NTR) and TrkA protein during the early stages of AD. Whether there is a concomitant reduction in cortical levels of these receptors during the progression of AD is unknown. p75(NTR) and TrkA protein was evaluated by quantitative immunoblotting in five cortical regions (anterior cingulate, superior frontal, superior temporal, inferior parietal, and visual cortex) of individuals clinically diagnosed with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD, or severe AD. Cortical p75(NTR) levels were stable across the diagnostic groups. In contrast, TrkA levels were reduced approximately 50% in mild/moderate and severe AD compared with NCI and MCI in all regions except visual cortex. Mini-Mental Status Examination scores correlated with TrkA levels in anterior cingulate, superior frontal, and superior temporal cortex. The selective reduction of cortical TrkA levels relative to p75(NTR) may have important consequences for cholinergic NB function during the transition from MCI to AD.

Aging of the brain, neurotrophin signaling, and Alzheimer's disease: Is IGF1-R the common culprit?

“…It is also worth noting that different studies have found a selective and marked reduction in the expression of cortical TrkA in early and late stages of AD, when compared to age-matched controls [30,68,111]. This seems to occur in the face of stable [30,68,111] or increased [72,113] p75 NTR , and increased pro-NGF [41,121].…”

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

“…TrkA, p75, Sortilin (Lu et al, 2005). While a marked decrease of TrkA is assessed in basal forebrain and in cortex (Chu et al, 2001;Mufson et al, 1996Mufson et al, , 1997Mufson et al, , 2000Salehi et al, 1996;Boissiere et al, 1997;Hock et al, 1998;Savaskan et al, 2000;Counts et al, 2004;Ginsberg et al, 2006), p75NGF receptor levels appear to be up-regulated (Hu et al, 2002), downregulated (Kerwin et al, 1992;Salehi et al, 2000;Mufson et al, 2002) or unchanged (Mufson et al, 2003;Ginsberg et al, 2006) in different models of aging and of AD. In addition, an unbalance in TrKA and p75 activity favoring the binding of NGF to p75 and the Ab mediated neuronal death has been recently reported in mild AD patients (Wu et al, 2007) and in in vitro AD neuronal models (Sotthinbundhu et al, 2008;Matrone et al, 2009).…”

Age-dependent loss of NGF signaling in the rat basal forebrain is due to disrupted MAPK activation

“…Therefore, investigators have been searching for additional biological markers. The loss of nerve growth factor (NGF) as well as its receptor has been implicated in the loss of cholinergic tone and function in AD and aging [14,33,34]. In MCI patients it was found that basal forebrain levels of TrkA decline 50% compared with age matched controls and that the number of TrkA immunopositive neurons in the basal forebrain correlate well with a number of different cognitive measures [33,34].…”