Amyloid plaques, neurofibrillary tangles and inflammatory events remain the key neuroanatomical markers of Alzheimer’s disease. In addition, AD is accompanied by a loss of nAChR expressing neurons throughout the basal forebrain, neocortex, hippocampus and entire cortical mantle. An increasing body of evidence suggests solid links between the classical AD markers and the loss of nicotinic receptors.
In addition to an elevated amyloid load, inflammatory events are believed to play a major role in neuro-degeneration and also in normal ageing. Cytokine activation of astrocytes may lead to enhanced Aß production and plaque formation. Nicotinic receptors have been shown to be expressed on astrocytes from rat brain and human brain.
Nicotinic receptor activation by agonist can modulate the expression of growth factors in vivo, such as basic fibroblast growth factor 2 (bFGF-2), brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), the latter two factors of which have been reported to modulate amyloid precursor protein (APP) expression and Aß production. Furthermore, nicotine-induced activation of the α7 nAChR has been shown to increase the expression of the high affinity receptor for NGF, TrkA, a loss of which is believed to be one of the earliest markers of neuronal dysfunction. In an animal model of NGF deprivation, nicotinic enhancement is able to reduce degeneration and cell death of neurons, formation of plaques and cognitive impairment. Although it is firmly established that nicotinic receptors represent essential elements of brain plasticity and cell survival, their exact involvement in AD pathology and neuro-protective mechanisms remains to be fully elucidated.