Cholinergic strategies for Alzheimer's disease

Alzheimer's disease is a devastating degenerative disorder of the central nervous system that results in gradual deterioration of cognitive function and severe alteration of personality. Degeneration of neurons in the nucleus basalis Meynert, the origin of the major cholinergic projections to the neocortex, occurs early in the course of the disease, and is correlated with the cognitive decline. This link between cholinergic dysfunction in the basal-cortical system and cognitive deficits has focused scientific efforts on developing tools to elucidate the neurobiological role of the cholinergic system in cognition and to develop therapeutic interventions in the disorder. An important step in understanding the mechanisms underlying cognitive dysfunction has been the development of in vivo rodent models that mimic some of the features of Alzheimer's disease. Acute excitotoxic or immunotoxic lesions of the nucleus basalis in rodents have revealed a role of the basal-cortical system in attention, learning and memory. More recent advances in developing mouse gene technology offer newer models to systematically examine the underlying neuropathological cascade leading to dysfunctions in mnemonic processing. Using in vivo rodent models, several cholinergic enhancement strategies have been tested and proven to be effective in alleviating lesion-induced cognitive deficits, including neuropharmacological approaches (acetylcholinesterase inhibitors), neurotrophic factor administration (nerve growth factor), and transplantation of cholinergic-enriched fetal grafts. Successful results have also been obtained using ex vivo gene transfer to deliver nerve growth factor or acetylcholine to compromised regions of the basal-cortical system. Gene therapy may be of particular interest for clinical applications, because this approach provides a method for topographically restricted and selective delivery of therapeutic genes and their products to afflicted areas of the brain. Advanced techniques in molecular biology (e.g., exogenous regulatable gene transfer) and newly developed tools of modern neuroscience (e.g., neural precursor cells) will be important contributions for deciphering the biological bases of neuronal degeneration and for refining therapeutic strategies for Alzheimer's disease.     

Cholinergic foundations of Alzheimer's disease therapy

Cholinesterase inhibitors (ChEI) represent the drug of choice for Alzheimer's disease (AD) treatment. They produce significant improvement on cognitive as well as non-cognitive function for a period up to 1 year during the first 3 years following clinical diagnosis. The magnitude of cognitive improvements is similar for different ChEI, however, differences are seen with regard to incidence and severity of side effects, optimal ChE inhibition, pharmacokinetic properties and mode of administration.     

Inflammatory mechanisms in Alzheimer's disease: implications for therapy

OBJECTIVE: The purpose of this article is to review evidence that inflammatory and immune mechanisms are important in the pathophysiology of Alzheimer's disease and to suggest new treatment strategies. METHOD: The authors review the English-language literature of the last 10 years pertaining to the pathophysiology of Alzheimer's disease. RESULTS: There is ample evidence supporting the hypothesis that inflammatory and immune mechanisms are involved in tissue destruction in Alzheimer's disease. Acute phase proteins are elevated in the serum and are deposited in amyloid plaques, activated microglial cells that stain for inflammatory cytokines accumulate around senile plaques, and complement components including the membrane attack complex are present around dystrophic neurites and neurofibrillary tangles. CONCLUSIONS: Clinical trials of anti-inflammatory/immunosuppressive drugs are necessary to determine whether alteration of these inflammatory mechanisms can slow the progression of Alzheimer's disease.     

Aging, Alzheimer's disease, and estrogen therapy

Experimental studies in vivo and in vitro, as well-retrospective studies in post-menopausal women suggest that taking estrogens for a number of years may reduce the risk to develop Alzheimer's Disease (AD). Because these conclusions are drawn mainly on the basis of retrospective studies, large, randomized, placebo-controlled trials are necessary before recommending use of estrogens to women for the prevention of AD.     

Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging

OBJECTIVE: To study the association of estrogen-replacement therapy and other estrogen-related variables with Alzheimer's disease in postmenopausal women. BACKGROUND: Postmenopausal estrogen use has been reported to lower the risk of Alzheimer's disease. DESIGN: A population-based, multicenter survey was carried out in eight Italian municipalities. The sample of 2,816 women, aged 65 to 84 years, was randomly selected from the population register of each municipality and stratified in 5-year age groups. All women were screened using the Mini-Mental State Examination and interviewed concerning risk factors. Those who screened positive underwent a clinical assessment. Dementia syndrome was diagnosed according to DSM-III-R criteria, and Alzheimer's disease was diagnosed according to NINCDS-ADRDA criteria for possible and probable Alzheimer's disease. RESULTS: The estimated prevalence of postmenopausal estrogen use adjusted to the 1991 Italian female population was 12.3%. The frequency of estrogen use was higher among nonpatients compared with Alzheimer's disease patients (odds ratio, 0.24; 95% confidence interval, 0.07 to 0.77). The inverse association between estrogen therapy and Alzheimer's disease remained significant after adjustment for age, education, age at menarche, age at menopause, smoking and alcohol habits, body weight at the age of 50 years, and number of children (odds ratio, 0.28; 95% confidence interval, 0.08 to 0.98). CONCLUSIONS: Our data from a population-based study support the hypothesis that estrogen-replacement therapy is associated with a reduced prevalence of Alzheimer's disease in postmenopausal women. Prospective clinical trials are required to enable women and their physicians to weigh risks and benefits of estrogen-replacement therapy for the prevention of dementia.     

Affective disorders in Alzheimer's disease

The links between depressive syndrome and Alzheimer's disease are problematic concerning the diagnosis and the therapeutic choice. The concepts of pseudo-dementia and late onset depression are shortly discussed. The hypothesis concerning the relationship between depression and Alzheimer's disease are summarized. The clinical data relevant for the diagnosis and the therapeutic guidelines are discussed.     

Mental-behavioral disorders in Alzheimer's disease

Behavioural and psychological disorders are often observed in Alzheimer's disease. Some are common, such as symptoms of depression, apathy, aggressivity, agitation, psychotic disturbances, disorders of sleep rhythm, etc. Many factors contribute to the aetiology of these disorders, mainly cerebral lesions, environmental changes, somatic illnesses, iatrogenic factors and psychological reaction mechanisms. Management must take each into account. Treatment comprises medication (symptomatic treatment of the various disorders, cholinergic treatment) and other means (adaptation of the inhabitation, informing family and friends, psychotherapy, etc.).     

Oxidative alterations in Alzheimer's disease

The expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), an EGF receptor ligand, was investigated in rat forebrain under basal conditions and after kainate-induced excitotoxic seizures. In addition, a potential neuroprotective role for HB-EGF was assessed in hippocampal cultures. In situ hybridization analysis of HB-EGF mRNA in developing rat hippocampus revealed its expression in all principle cell layers of hippocampus from birth to postnatal day (P) 7, whereas from P14 through adulthood, expression decreased in the pyramidal cell layer versus the dentate gyrus granule cells. After kainate-induced excitotoxic seizures, levels of HB-EGF mRNA increased markedly in the hippocampus, as well as in several other cortical and limbic forebrain regions. In the hippocampus, HB-EGF mRNA expression increased within 3 hr after kainate treatment, continued to increase until 24 hr, and then decreased; increases occurred in the dentate gyrus granule cells, in the molecular layer of the dentate gyrus, and in and around hippocampal pyramidal CA3 and CA1 neurons. At 48 hr after kainate treatment, HB-EGF mRNA remained elevated in vulnerable brain regions of the hippocampus and amygdaloid complex. Western blot analysis revealed increased levels of HB-EGF protein in the hippocampus after kainate administration, with a peak at 24 hr. Pretreatment of embryonic hippocampal cell cultures with HB-EGF protected neurons against kainate toxicity. The kainate-induced elevation of [Ca2+]i in hippocampal neurons was not altered in cultures pretreated with HB-EGF, suggesting an excitoprotective mechanism different from that of previously characterized excitoprotective growth factors. Taken together, these results suggest that HB-EGF may function as an endogenous neuroprotective agent after seizure-induced neural activity/injury.