Studying of Alzheimer's Disease

Introduction

AlzheimerÐŽ¦s disease (AD) was first reported and named after the patient in 1907, Alois Alzheimer. It is the leading cause of dementia in the world, affecting 12 million people worldwide. Symptoms of the disease include memory loss, temporal and geographic disorientation, resulting failure to maintain balance of self, impairment of judgment, deterioration of problem solving, and deterioration of language abilities. AD is caused by the formation of plaque and neurofibrillary tangles (NFTs) leading to extensive neuron death in the brain and results in a destructive pathway. Some other factor causing AD are over expression of amyloid precursor protein (APP), presenilins, or tau protein genes to cause the over-production and build up of the plague. This paper explores these neuro-pathological problems that leads to the developing of AD in rodent transgenic animal and non-rodent transgenic animal such as the fruit fly Drosophila melanogaster and the nematode Ceanorhabditis elegant to learn from and develop treatment and therapy for the human condition (Spires and Hyman, 2005).

WhatÐŽ¦s wrong in the Alzheimer brain

In 1927 Divry showed that the senile plaques in the AlzheimerÐŽ¦s brain is a spherical mass of amyloid fibrils, which is an extracellular aggregation of amyloid that is later on discovered to be derived from the APP by Kang et al. in 1987. In the AlzheimerÐŽ¦s brain, plague formation usually starts first from the basal neocortex of the brain and then spread to the hippocampal formation and adjoining cortical areas of the brain.

Formation of NFTs is another known cause of AD. The neurofibrillary tangles first form in the transentorhinal region and spread through to the entorhinal cortex, hippocampus, association cortex and sensory cortex. This eventually leads to the degradation of temporal lobe memory system and contribute to the memory loss symptom. The density of the NFT is directly related to the disease duration and the severity of dementia. Formation of NFT also mirrors the progression of extensive neuron loss; correspondingly, a case of large-scale loss of neuron will show more dramatic display of the AD symptoms. The remaining neuron in the brain undergoes changes that alter the connectivity in the circuit of dendrite and cell body, resulting in the loss of synapses relates to the cognitive decline.

Amyloid Pathology Mouse Models

The over expression of APP in amyloid pathology can cause AD. In 1995, PDAPP mouse was introduced to use as a study tool for AD, these mice over expressed human APP cDNA that had a higher level of APP protein expression by ten fold in comparison to normal mouse. The PDAPP mice expressed very similar property that of the AD in ultra structures, pathway of plaque formation, and even the degeneration of memory by testing with maze task with increase aging.

Other lines of mouse with similar over express of human APP has been developed with slight different mutation or different promoter control for the amyloid precursor protein. These other transgenic mouse shows difference in percentage of neuron loss and plaque formation at different age, however they all show the general memory deficits symptoms expressed like the AD.

Interaction of presenilin and APP

APP mutations only cause a fraction of the reason for familial AD. It is believed that mutation in presenilins1 and 2 can also contribute to the cause of AD by altering the process of APP to favor the production of the fibrillogenic AЈ]42. Crossing of mutant presenilin 1 with Tg C3-3 APP line of mice increase the AЈ]42 level in the brain and cause accelerated formation of plaque. The AD thatÐŽ¦s associated with the mutation of presenilins have a higher probability of producing the AЈ]42 amino acid that is harmful, making presenilins a drug target to allow further experiment to develop treatment that can decrease amyloid deposition in AD patients.

Tau transgenic mouse models

The tau protein binds microtubules, polymerizes actin, and it is involved in intracellular trafficking, it is usually located in axons in the brain. In the AD brain, it is found in cell bodies and dendrites as well as axons. The mutation in the tau protein reduces its binding ability to microtubules or alters the exon splicing resulting in increased repeat tau isoforms.

Over expressing of tau protein showed formation of hyperphosphorylation of tau and axonal pathology. This is insufficient to induce NFTs but it does induce muscle weakness. A new pathogenic tau mutation (P301L) is later discovered that express the shortest four repeat tau isoform under the mouse prion promoter caused NFTs formation. These mice developed motor deficits and cell loss along with decline in performance in the maze indicating the effect of memory degeneration.

Tau transgenic model in combination with APP over expressing mice provide ways to study the disease mechanism and develop treatment on these mice.

Nonrodent transgenic models

Invertebrate model have very different brain anatomy from mammals that they are not very accurate reproductions of the AD pathology for our consideration, but their low cost, small size, short life span characteristics make them very good for drug screening and cell biology associated with pathogenesis of AD. Two common ones are the study of fruit fly Drosophila melanogaster and nematode Ceanorhabditis elegans.

These invertebrate models have homolog of APP named amyloid precursor protein-like and they are similar to APP except the AЈ] region. Over expression of these protein showed that in the body wall muscle induces progressive paralysis and shortens life span. They both express presenilin, which has contributed to the identification of many complexes that affect the study of AD such as APH1, Ј^-secretase complex, and PEN1.

Tau has also been studied in both of these organism and the neuronal dysfunction, synaptic abnormalities, and disrupted axonal transport are observed with the mutant tau they express.

Treatments arising from animal studies

One of these is the using of Ј^-secretase inhibitor to lower AЈ] level to treat the plaque build up. However lowering the AЈ] level also has its side effects in gastrointestinal tract. Other treatments include Ј]-secretase and using metal ion to help reduce the AЈ] deposition.

The most promising treatment so far is the immunotherapy treatment, by immunization of the mice with AЈ]42; it prevented the development of amyloid pathology or reduces the extent of it if already in existence. Experiments even