Target Discovery and Validation Reviews and Protocols

Transgenic Models 187
period of incubation. AD is characterized by the extracellular accumulation of
polymerized tau protein. β-Amyloid is cleaved from amyloid precursor protein
(ADP), the cleavage being performed by three secretases: -α, -β, and -γ (126).
Transgenic mice, in which the ADP gene had been knocked out, kept their sensitivity
to the disease (127) because of the presence of another gene called
ADP-like gene. The knockout of the gene is lethal. Transgenic mice with
knocked-out ApoE and IL1 genes are less sensitive to the disease, indicating
that these two genes contribute to AD development.
Different models have been obtained. Some of the models overexpress normal
APD and prenisilin genes, whereas other models express mutated forms of
the genes. None of these models reflect all the aspects of AD. Fewer neurons in
generals are destroyed in the models than in patients. Correlation between
behavioral disorders and accumulation of β-amyloid is not always strict. Yet,
the models show a similar disease pattern, and they may therefore help to identify
active molecules and to design analogs capable of reaching the brain (128).
4.6. Models for Degenerative Diseases
Degenerative diseases generally have slow development, and transgenic
models may be helpful to decipher their mechanisms, not only for Alzheimer’s
disease but also for prion diseases and other pathologies. Prion diseases would
be much less well understood without the contribution of transgenic mice
(129,130). Creutzfeldt–Jakob and related diseases are typically pathologies,
which incubate for very long periods and require the cooperation of several cell
types, especially when infection occurs by the oral route. It was essential to
show that the PrP–/– mice were insensitive to any prion infection, which then
demonstrated that the PrP gene has a major role in prion diseases.
Transgenic mice overexpressing the PrP genes from different species
become more sensitive to the prion disease of the same species. This phenomenon
is amplified when the endogenous mouse PrP gene is knocked out. For
example, PrP–/– mice expressing the bovine PrP gene are sensitive to bovine
spongiform encephalopathy (131). PrP–/– mice expressing the hamster PrP
gene specifically in astrocytes are sensitive to hamster scrapie (132). Transgenic
mice also revealed that some epitopes of the PrP protein are essential for the
transmission of the disease (133), that some PrP alleles are more favorable for
injection than others, and that genetic environmental factors modify the incubation
period of bovine spongiform encephalopathy (134).
The prion disease manifests more rapidly when the PrP gene of the mouse
and the cell extract used for infection come from more closely related species.
It was also surprising to observe that the cell extracts become increasingly
infectious after repeated passages to animals. This adaptation has not yet been