Genetic models

The identification of gene mutations with linkage to early-onset AD (EOAD) provided an approach to studying the pathophysiology of autosomal dominant familial disease. Transgenic mice and rats have been developed that express the APP and/or the presenilins (PS1, PS2) with familial AD mutations. An array of pathology is observed in these animals, including amyloid deposition in diffuse and core plaques, dystrophic neuritis, and inflammatory gliosis. Widespread neurodegeneration is however not prevalent and NFT formation is absent, although immunohistological and biochemical analyses reveal phosphorylated and high-molecular-weight insoluble tau.25 The Tg2576 model, the Hsaio mouse, introduced in 1996, was cross-bred to animals transgenic for PSl-containing FAD mutations. The mutant PS1 gene on the Tg2576 mouse accelerated the time course of amyloid deposition. Transgenic animals harboring mutations (P301L) in the tau protein gene responsible for FTDP exhibit motor and behavioral deficits and show age and gene dose-dependent development of NFTs in the spinal cord and in some (amygdala, septal nuclei, hypothalamus, midbrain, pons), but not all, brain regions (cortex, hippocampus, basal ganglia). Mice expressing both tau and APP familial AD mutations show enhanced development of NFTs in different brain regions, depending on whether there are single or multiple mutations in the tau gene. Reduced neuron numbers in both the cortex and hippocampus occur in double transgenic mice with multiple tau mutations. In triple transgenics with mutant APP, PS1, and tau proteins, synaptic dysfunction is evident early on and hallmark lesions (senile plaques and NFTs) follow a similar pattern of progression and expression in brain regions predominantly affected in AD. A more recent study using the Tg2576 AD mouse model showed decreases in dendritic spine density, impairment of long-term potentiation (LTP) and behavior that occurred several months before plaque deposition.26 Decreases in spine density in the outer molecular layer of the dentate gyrus occurred at 4 months of age while plaque deposition did not occur until 12-18 months, re-emphasizing the need to study new treatment modalities designed to arrest disease progression at markers distinct from plaque formation when their efficacy may be limited. Despite the genetic sophistication of these mouse models, there are no NCE back-validated models of AD in human.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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