Procedural learning


Procedural learning


Alzheimer's Disease

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The occurrence of Alzheimer's disease, the most common cause of (senile) dementia (about 70%), is favored by a genetic disposition. However, the disease is not genetically uniform. An especially severe form of the disease has an autosomal dominant inheritance. Defects on chromosomes 1, 12, 14, 19, or 21 were found in families with Alzheimer's disease. The defective gene on chromosome 19, for example, codes for apolipoprotein E (ApoE 4), the relevant gene on chromosome 21 for a protein (p-amyloid precursor) that can be broken down to small amyloid peptides. These can on their own bunch themselves together into protein fibrils 7-10nm long (^A1). These amyloid fibrils can then form aggregates, 10 |m to several hundred |m in diameter (senile plaques), that are frequently found in the brain of patients with Alzheimer's disease (^ A2). In addition to extracellular amyloid, these plaques contain distorted dendrites and axons with abnormal intracellular neurofibrils. The formation of these atypical elements of the cytoskeleton apparently precedes the death of the neurons (see below).

Certain mutations of the p-amyloid precursor gene promote the formation of senile plaques. Amyloid deposits can also occur under the influence of other genetic or external factors. It is thought, for example, that toxins can penetrate the brain via the olfactory nerves and cause the disease. Amyloid deposits also occur in trisomy 21 (Down's syndrome) that also leads to dementia.

p-amyloid fibrils can react with receptors at the cell surface, such as the receptor for advanced glycation end products (RAGE), and a scavenger receptor (RA). Oxygen radicals formed as a result may increase the neuronal intracellular concentration of Ca2+ (^A3), possibly via depolarization of the cell membrane and activation of NMDA receptors. The O2 radicals and Ca2+ promote cell death. In microglial cells (^ A4) the activation of RAGE and RA stimulates the formation or release, respectively, of NO, prostaglandins, excitotoxins, cy-tokines, tumor necrosis factor (TNF-a), tumor growth factor (TGF-P1), and fibroblast growth factor (b-FGF). This results in inflammation that also impairs neurons. Increased concen tration ofthe osmolyte inositol points to a disorder ofcell volume regulation.

The death of neurons is accelerated by a lack of NGF or of NGF receptors and can be delayed by NGF.

Cholinergic neurons in the basal nucleus of Meynert, in the hippocampus (especially CA1, the subiculum) and in the entorhinal cortex (^ B1) are particularly affected by cell death, but neurons also die in other cerebral areas, such as the frontal lobes, anterior temporal lobes, parietal lobes, olfactory cortex, hypothalamus, locus ceruleus, and raphe nuclei.

Neuronal death is accompanied by decreased formation and concentration ofneuro-transmitters in the brain. Acetylcholine is markedly affected: in the cerebral cortex and the hippocampus there is an up to 90% decrease in the concentration of choline-acetyl transferase, the enzyme that is necessary for the formation ofacetylcholine. The concentration of other neurotransmitters is also reduced, forexample, norepinephrine, serotonin, somatotropin, neuropeptide Y, substance P, and corticotropin-releasing hormone ([CRH] corticoliberin).

A consequence of the degenerative changes is an increased loss of cerebral functions (^ B2). The disease typically begins insidiously with subtle deficits of memory, neglect of appearance and body hygiene, phases of confusion, and taking wrong decisions. As the disease progresses, anterograde amnesia (^ p. 346) will be followed by impairment of past memories as well as procedural memory. Lesions in the limbic system express themselves alternately through restlessness and lethargy. Motor deficits (speech disorders, abnormal muscle tone, ataxia, hyperkinesia, myoclonus) occur relatively late.

Creutzfeldt-Jakob disease, possibly caused by prions (proteinaceous infectious particles), is a neurodegenerative disease that, in addition to motor (e.g., ataxia) and psychogenic disorders, also leads to dementia.

I— A. Causes of Alzheimer's Disease

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