paper3

THE DISEASE AND ITS TREATMENT

Pathology of Alzheimer’s disease: Highlights from the World Alzheimer’s Congress 2000

In order to better understand the current knowledge on Alzheimer’s disease, I made an extensive summary from selected chapters out of a review paper reporting on the information presented at the World Alzheimer’s Congress2000. (Jan Favre, October 2000) The full report, supported by an educationgrant from Janssen and Novartis can be retrieved at the following Web Site:
http://www.medscape.com/Medscape/CNO/2000/WAC/public/Conference.cfm?conference_id=63

Basic pathology

The Alzheimer’s disease brain pathology is characterized by two factors:

Plaques which are extracellular bodies, consisting inthe deposition of A-beta proteins
Tangles which are filamentous intra-neuronal bodies consistingin hyperphosphorylated microtubules associated protein tau (PH-tau). Theyare a dense mass of thread-like substance (neuropil threads).

There seems to be a significant correlation of the density of tangles and the clinical expression of the disease whereas the relationship of plaque density and severity of the disease appears to be less evident.
There is a normal metabolic pathway in which alpha-secretases cleavethe APP (Amyloid Precursor Protein) into useful metabolic components. However,the alternate pathway, mediated by beta- and gamma-secretases, leads tothe amyloidogenesis and to A-beta-proteins. Aggregated and fibrillar formsof A-beta-proteins characterize the end stage of the disease where onecan observe by post-mortem anatomical brain preparations amyloid plaquesassociated microglia and swollen neurites.

Amyloid Precursor Protein (APP)

Several gene mutations are associated to Alzheimer’s disease. Let usmention the APP gene mutations in chromosome 21, which are related to familialcases of Alzheimer’s disease. Mutations in the presenilin-1 (PS-1) genein chromosome 14 and presenilin-2 (PS-2) gene on chromosome 1 is relatedto the familial early-onset Alzheimer’s disease. Presenilins are involvedin the regulation of intra-membranous proteolysis.
APOE genotype is associated to the late onset Alzheimer’s disease,which affect the majority of Alzheimer’s patients. In particular, it hasbeen observed that the presence of epsilon 4-allele lead to the accelerationof A-beta-protein deposition. A-beta protein is involved in transport andmetabolism of cholesterol and other fats. A high fat diet can stimulatethe production of APP- and A-beta-proteins. The toxic effect of A-beta-proteinstarts very early, well before the appearance of plaques as seen in animaland in-vitro models, in the disease process, which leads then first toMild Cognitive Impairment and then to Alzheimer’s disease. The appearanceof tangles seems to come later in the disease process.

Tau-protein

Tau-proteins seem to be fundamental for the assembly and stabilization of microtubules. But abnormal Tau-protein leads to tangle formation, particularly within the medio-temporal lobe. An unbalanced ratio of kinases/phosphatases, modulating the phosphorylation of tau-proteins leads to the cumulationof hyperphosphorylated tau-proteins, followed by the genesis of tangles.However the appearance of a few tangles in the brain with no or some senileplaques is associated with normal aging. Moderate and high density of tanglesand senile plaques are found in the brain of patients suffering from eitherMild Cognitive Impairment (moderate density) either from Alzheimer’s disease (high density).

According to studies in non-human primates, A-beta-protein may stimulate the phosphorylation of tau-protein, which leads to the formation of tangles. Thus, A-beta-protein may be the common cause of tangles and plaques, which allow to consider a unifying hypothesis of Alzheimer’disease genesis.

Inflammation and oxidative stress

The brain of patients with Alzheimer’s disease has a chronic inflammatory response to tangles and plaques. Fibrillar A-beta-proteins activate microglia. The activated microglia produce 2 factors:

Macrophage stimulating factor
Complement components (serene proteases)

These combined factors lead to the Membrane Attack Complex (MAC), whichproduces pore in cell membranes, thus leading to their death. Stimulatedmicroglia produce also the initiating complement factor Ciq, which bindto A-beta-proteins and thus promote its aggregation leading to senile plaques.
The inflammation induces the oxidative stress where the end productsare lipid peroxides, which are very aggressive tissue destructors. Oxidativestress also affect mitochondria. Altered mitochondria produce additionaloxidative agents.
These phenomena provide us the rational of antiinflammatories and antioxidants, being potentially useful drugs in slowing the disease progression.

Pathology of the cholinergic system

According to recent studies, the loss of cholinergic neurons seem toappear relatively late in the disease progression since they are relatively preserved in patients with Mild Cognitive Impairment and in those withmild Alzheimer’s disease. However in the early phase of the disease, the cholinergic neurons of affected patients markedly loose calbindin-D activity (calcium binding protein present in the majority of the basal forebraincholinergic neurons). They loose also their affinity to certain protectivenerve growth factors. Furthermore, altered forms of cholinesterases mayplay a role in the pathogenesis of plaques and tangles. This leads to thehypothesis that acetylcholinesterase inhibitors, which possibly correctthe unbalanced metabolisation of acetylcholine in the brain of patientssuffering from Alzheimer’s disease, could in fact retard the disease progression.

E-mail: [email protected]

Hosted by www.Geocities.ws