Pre- and post-synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer’s disease

Abstract

Amyloid imaging has identified cognitively normal older people with plaques as a group possibly at increased risk for developing Alzheimer’s disease-related dementia. It is important to begin to thoroughly characterize this group so that preventative therapies might be tested. Existing cholinotropic agents are a logical choice for preventative therapy as experimental evidence suggests that they are anti-amyloidogenic and clinical trials have shown that they delay progression of mild cognitive impairment to dementia. A detailed understanding of the status of the cortical cholinergic system in preclinical AD is still lacking, however. For more than 30 years, depletion of the cortical cholinergic system has been known to be one of the characteristic features of AD. Reports to date have suggested that some cholinergic markers are altered prior to cognitive impairment while others may show changes only at later stages of dementia. These studies have generally been limited by relatively small sample sizes, long postmortem intervals and insufficient definition of control and AD subjects by the defining histopathology. We therefore examined pre- and post-synaptic elements of the cortical cholinergic system in frontal and parietal cortex in 87 deceased subjects, including non-demented elderly with and without amyloid plaques as well as demented persons with neuropathologically-confirmed AD. Choline acetyltransferase (ChAT) activity was used as a presynaptic marker while displacement of 3H-pirenzepine binding by oxotremorine-M in the presence and absence of GppNHp was used to assess postsynaptic M1 receptor coupling. The results indicate that cortical ChAT activity as well as M1 receptor coupling are both significantly decreased in non-demented elderly subjects with amyloid plaques and are more pronounced in subjects with AD and dementia. These findings confirm that cortical cholinergic dysfunction in AD begins at the preclinical stage of disease and suggest that cholinotropic agents currently used for AD treatment are a logical choice for preventative therapy.

Predominant loss of glutamatergic terminal markers in a β-amyloid peptide model of Alzheimer's disease

“…There is ample evidence for a cholinergic dysfunction associated with memory impairment (Bartus et al, 1982), in particular with AD (Auld et al, 2002), as heralded by the observations that Ab can decrease the evoked release of acetylcholine from hippocampal slices (Kar et al, 1996) and that there is a decreased ability to trigger acetylcholine release in cortical samples from demented individuals (Sims et al, 1983). Several studies in humans and in animal models of AD showed that the modification of the cholinergic system is an early event, already measurable at pre-symptomatic stages of AD (Watanabe et al, 2009;Potter et al, 2011;Zhang et al, 2012; but see Davis et al, 1999). However, there is some debate as to whether the changes are compensatory or part of the disease mechanism.…”

Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT

“…These changes thus may reflect a compensatory response to maintain basocortical cholinergic function given that loss of pre-synaptic receptors usually results in compensatory up-regulation of post-synaptic receptors [35]. Alternatively, the relative preservation or increase may also be the result of a postulated bidirectional modulatory effect between beta amyloid and M1 receptors in the frontal and parietal areas [41].…”

“…Cholinergic changes may manifest even at the preclinical stage [41], although others have demonstrated that in early stages of AD, cholinergic neurons in the basal forebrain are relatively preserved [15,21]. Nevertheless, remediation of cholinergic function, in the form of cholinesterase inhibitors (AChEIs), has been the mainstay of symptomatic treatment in AD for many years.…”

Neuropathology of Dementia Disorders

“…Previously defined as the manifestation of deteriorating brain functions over time due to cell deaths in the brain caused by neurodegeneration or any other disease [3], according to recent research dementia is not primarily caused by neuronal cell death/loss, but by dysfunction and loss of synapses [4] in AD [5] and in α-synucleinopathies [6]. Other causes include cholinergic neuronal and axonal abnormalities [7,8], as well as pre-and postsynaptic cortical cholinergic deficits also occurring in early AD [9]. These changes due to disconnection of major nervous circuitries causing default networks [10][11][12][13] have been demonstrated in vivo in early AD [14], suggesting that disease progress is transmitted by neuronal pathways [15].…”