Functional Genomics Research
Alzheimer's disease
Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by synaptic dysfunction, neuronal loss and cognitive decline. The main lesions in the brains of AD patients are neruofibrillary tangles and neuritic plaques, which are mainly composed of β-amyloid peptide (Aβ), which is formed by proteolysis from the amyloid precursor protein APP. APP is a single-pass transmembrane protein that is processed in two different ways: α-secretase cleaves APP within the Aβ region, preventing Aβ formation and releasing APPsα ectodomain; in the amyloidogenic pathway, APP is sequentially cleaved by β- and γ-secretase, leading to Aβ formation. While the mechanisms of Aβ formation have been intensively studied, the physiological role of APP and its numerous proteolytic fragments and whether loss of these functions contributes to Alzheimer's disease is still unknown.
Knockout mice with single or combined genetic defects of APP family proteins
Determining the in vivo functions of APP in mammals is complicated by the presence of two APP-related genes, APLP1 and APLP2. APP and APLP share two conserved domains in the extracellular region (E1 and E2) and one in the cytoplasmic domain, while the β-amyloid peptide is absent in APLP. Therefore, functional redundancy can compensate for the loss of essential gene functions, e.g. in knockout (KO) models. Indeed, by generating different KO mutants, we were able to show that the high structural similarities between APP and APLPs are also reflected at the functional level. Mice in which APP, APLP1 or APLP2 is inactivated are viable, and APP KO mice exhibited reduced brain and body weight, decreased grip strength, altered locomotor activity, increased susceptibility to seizures, and a defect in spatial learning and LTP. In contrast to viable single mutants, combined APLP2-/-APP-/- and APLP2-/-APLP1-/- double mutants die shortly after birth, suggesting that the APP family proteins fulfill redundant functions essential for viability (Heber et al., 2000). While the brains of double knockout animals show no obvious morphological defects, triple mutants lacking the entire APP gene family show cranial dyspalias resembling human lissencephaly type II (Herms et al., 2004). In the affected areas, neuronal cells from the cortical plate migrated beyond their normal position and protruded into the marginal zone and subarachnoid space. APP/APLPs thus play a crucial role in the adhesion and positioning of neurons. This role in cell adhesion is also supported by data from a recent collaborative study showing that APP family proteins form cis- and trans-dimers that are involved in cell adhesion, and thus may play a role in synaptic differentiation/function (Soba et al. 2005). Overall, our data indicate that APP family members play an essential role in normal brain development and early postnatal survival. Work is currently underway to circumvent early lethality and assess function postnatally by generating tissue-specific knockouts.
