The cholinergic hypothesis of Alzheimer's disease: a review of progress

Abstract

Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research eVort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and eVective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed eYcacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors. (J Neurol Neurosurg Psychiatry 1999;66:137-147) Keywords: acetylcholine; Alzheimer's disease; cholinesterase inhibitors; treatment Alzheimer's disease aVects an estimated 15 million people worldwide and is the leading cause of dementia in elderly people. With the proportion of elderly people in the population increasing steadily, the burden of the disease, both to carers and national economies, is expected to become substantially greater over the next 2 to 3 decades.Alzheimer's disease is a progressive neurodegenerative disorder with a mean duration of around 8.5 years between onset of clinical symptoms and death. Brain regions that are associated with higher mental functions, particularly the neocortex and hippocampus, are those most aVected by the characteristic pathology of Alzheimer's disease. This includes the extracellular deposits of -amyloid (derived from amyloid precursor protein; APP) in senile plaques, intracellular formation of neurofibrillary tangles (containing an abnormally phosphorylated form of a microtubule associated protein, tau), and the loss of neuronal synapses and pyramidal neurons. These changes result in the development of the typical symptomology of Alzheimer's disease characterised by gross and progressive impairments of cognitive function and often accompanied by...

Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells

“…A number of studies have demonstrated that vestibular stimulation can improve cognition in humans (reviewed in [91][92][93]). Given that synaptic plasticity is altered in patients with Alzheimer's disease [94] and degeneration of basal forebrain cholinergic neurons is a pathological hallmark of this disease [14,15,95,96], vestibular stimulation may provide a novel treatment to improve hippocampus-dependent cognitive deficits in affected patients.…”

“…However, a few experiments in which a short (<15 s) afterdischarge was evoked were included, since the magnitude of LTP (expressed at a ratio of the baseline) was similar to experiments without afterdischarge [42]. Following tetanus, AEPs were recorded at "fixed" times at 5,10,15,20,30,60,90,120,150 and 180 min. Previous data showed that LTP magnitude was not significantly different among test pulses of 1.5-2× fEPSP threshold intensity [43]; therefore, all AEPs were recorded with test pulse of 1.5× the fEPSP threshold.…”

“…Selective ablation of septal cholinergic neurons by intraseptal microinjection of the immunotoxin 192 immunoglobulin G-saporin (192 IgG-saporin) caused spatial learning and memory impairments in some [8][9][10] but not all experiments [11][12][13]. The cholinergic hypothesis of Alzheimer's disease postulates that degeneration of cholinergic neurons in the basal forebrain including the MS contributes to the cognitive deficits of Alzheimer's disease [14,15].…”

Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

“…In human volunteers, the pattern of cognitive impairment caused by scopolamine mimics in some aspects the cognitive symptomology seen in Alzheimer's disease (AD) (Ebert and Kirch, 1998) which is associated with the degeneration of cholinergic neurons in the basal forebrain resulting in a reduction of cholinergic neurotransmission in the forebrain (Araujo et al, 1988;DeKosky et al, 1996;Kuhl et al, 1999;Shinotoh et al, 2000;Shiozaki et al, 1999;Whitehouse et al, 1982). On the other hand, acetylcholinesterase (AChE) inhibitors, which increase synaptic acetylcholine (ACh) levels, are effective in the treatment of some cognitive symptoms of AD (Francis et al, 1999).…”

“…In addition to a deficit in cholinergic transmission, dementia is also related to degeneration of glutamatergic hippocampal and cortical pyramidal neurons (Aronica et al, 1998;Francis et al, 1999), which are targets for cholinergic and serotonergic innervation. Furthermore, the activity of glutamatergic neurons in the hippocampus and neocortex is modulated by cholinergic systems, which have facilitatory effects mediated via muscarinic receptors (Cole and Nicoll, 1984;Segal, 1982), and serotonergic systems, which have inhibitory effects partly mediated via 5-HT 1A receptors (Beck et al, 1992;Davies et al, 1987;Newberry et al, 1999;Pugliese et al, 1998).…”