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Alzheimer Genes in Cortical Development: How Do Their Prenatal Functions Relate to Dementia?
Jie Shen led this live discussion on 12 July 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.  View Transcript of Live Discussion — Posted 28 August 2006
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By Jie Shen
More than 80 mutations in the presenilin genes (PS1 and PS2) and about ten mutations in the gene encoding the amyloid precursor protein (AβPP) have been linked to familial Alzheimer's disease. These proteins—particularly the presenilins—play essential roles in cortical development. This raises fascinating questions about the role of neurogenesis, both during development and in the adult, in normal and pathological aging.
Mice lacking both PS1 and PS2 die before embryonic day 9 (Donoviel et al., 1999). PS1-/- mice, which are a partial loss-of-function presenilin mutant, do survive until birth and so permit us to assess PS1 function in neural development (Shen et al., 1997). Further analysis of PS1-/- mice revealed that PS1 is involved in the maintenance of the progenitor cell population and the regulation of neuronal differentiation through the Notch signaling pathway (Handler et al., 2000). In the absence of PS1, neural progenitor cells prematurely exit the cell cycle to differentiate into postmitotic neurons, thus depleting the pool of self-renewing progenitor cells needed for further brain development. By contrast, inactivation of PS1 in epidermal cells promotes hyperproliferation and tumorigenesis via the Wnt signaling pathway (Xia et al., 2001). These intriguing results suggest that PS1 may be directly involved in cell cycle regulation in a context-dependent manner. Since the PS1-null mutation represents only a partial loss of function of presenilins, a full characterization of presenilin function in neural development and the cell cycle still awaits the generation and analysis of cell type-specific, conditional null mutants of presenilins.
AβPP has been implicated in neuronal differentiation based on its expression pattern in vivo and in cultured neurons (Hung et al., 1992). And yet, there has not been direct evidence demonstrating an involvement of AβPP in neural development. APP-/- mice are viable and exhibit impaired learning and reduced locomotor activity (Muller et al., 1994; Zheng et al., 1995). Mice lacking either the amyloid precursor-like protein 1 or 2, (APLPs are members of the AβPP family,) are viable. However, APP-/-; APLP2-/- and APLP1-/-; APLP2-/- exhibit early postnatal lethality, indicating functional redundancies among these proteins (von Koch et al., 1997; Heber et al., 2000). However, the fact that the YENPTY motif at the C-terminal region of AβPP interacts with the PTB domain of mDab1, which is a key molecule in neuronal migration and cortical lamination, suggests that AβPP might be involved in the regulation of cortical lamination during development. Functional redundancies among AβPP family members may explain the lack of phenotypes in neural development in the single and double knockout mice. Mice lacking all three members of the AβPP family will determine whether the AbPP family is indeed involved in cortical development.
The fact that presenilins regulate neurogenesis has raised the question of whether FAD-linked mutations in presenilins lead to an impairment of neurogenesis, and to the subsequent question of whether defective neurogenesis contributes to the pathogenesis of AD. Fortunately, these questions can be addressed directly using a PS1 knockin mouse, in which a FAD-linked mutation is introduced into the PS1 gene in such a way that heterozygous knockin mice genetically resemble FAD patients (Guo et al., 1999). We are in the process of studying such mice, and their complete analysis will help us understand why genes involved in cortical development play a critical role in Alzheimer's disease.
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