The amyloid precursor protein and postnatal neurogenesis/neuroregeneration

doi:10.1016/j.bbrc.2005.12.150

Biochemical and Biophysical Research Communications

Volume 341, Issue 1, 3 March 2006, Pages 1-5

https://doi.org/10.1016/j.bbrc.2005.12.150 Get rights and content

Abstract

The amyloid precursor protein (APP) is the source of amyloid-beta (Aβ) peptide, produced via its sequential cleavage β- and γ-secretases. Various biophysical forms of Aβ (and the mutations of APP which results in their elevated levels) have been implicated in the etiology and early onset of Alzheimer’s disease. APP’s evolutionary conservation and the existence of APP-like isoforms (APLP1 and APLP2) which lack the Aβ sequence, however, suggest that these might have important physiological functions that are unrelated to Aβ production. Soluble N-terminal fragments of APP have been known to be neuroprotective, and the interaction of its cytoplasmic C-terminus with a myriad of proteins associates it with diverse processes such as axonal transport and transcriptional regulation. The notion for an essential postnatal function of APP has been demonstrated genetically, as mice deficient in both APP and APLP2 or all three APP isoforms exhibit early postnatal lethality and neuroanatomical abnormalities. Recent findings have also brought to light two possible functions of the APP family in the brain-regulation of neural progenitor cell proliferation and axonal outgrowth after injury. Interestingly, these two apparently related neurogenic/neuroregenerative functions of APP involve two separate domains of the molecule.

Section snippets

APP and proliferation of adult neural progenitors at the subventricular zone

The non-amyloidogenic sAPP had been implicated in enhancement of synaptogenesis, neurite outgrowth, and neuronal survival. In particular, sAPP has been known for some time now to be able to stimulate the proliferation of neural progenitor cells in culture [21], [22], as does the ectodomain of APLP-2 [23]. A possible role for the N-terminus of APP in stem cell growth has received support in that crystal structure analysis at 1.8 Å resolution of the cysteine-rich N-terminal heparin-binding domain

APP, postdevelopmental neurite arborization and neuronal regeneration after injury

It is amazing how much we have learned about various aspects of nervous system development from invertebrate models. In a recent report, Leyssen et al. [42] had, however, used a Drosophila model to unveil a postnatal function of APP. The neurons they focused on are sLNv, a well-characterized group of Drosophila brain neurons which regulates circadian rhythm. These have a simple and stereotypical morphology and therefore allowed high resolution microscopic analysis of axonal arborization

Epilogue

The evolutionary conservation of the APP and related genes is best explained by their products serving an important developmental or postnatal function. Genetic analysis clearly illustrates, in spite of obvious redundancy, the importance of APP and APLPs in postnatal function. The in vivo studies discussed here opened up new avenues to further explore the role of APP family members in postnatal neurogenesis as well as axonal regeneration after injury. Of course, attempts to study endogenous,

Acknowledgments

Work on neuronal death and regeneration in BLT’s laboratory is supported by research Grant No. 03/1/21/19/247 from the Agency for Science, Technology and Research (A*STAR)’s Biomedical Research council (BMRC).

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MinireviewThe amyloid precursor protein and postnatal neurogenesis/neuroregeneration

Abstract

Section snippets

APP and proliferation of adult neural progenitors at the subventricular zone

APP, postdevelopmental neurite arborization and neuronal regeneration after injury

Epilogue

Acknowledgments

Neurochem. Int.

Cytokine Growth Factor Rev.

Neuron

Curr. Opin. Neurobiol.

Neurobiol. Aging

Prog. Neurobiol.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Prog. Neurobiol.

Eur. J. Cell Biol.

Biological roles of APP in the epidermis

J. Biol. Chem.

Neuron

Int. J. Biochem. Cell Biol.

J. Biol. Chem.

Brain Res. Rev.

The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor

Nature

Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease

Science

The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics

Science

A modified beta-amyloid hypothesis: intraneuronal accumulation of the beta-amyloid peptide—the first step of a fatal cascade

J. Neurochem.

The synaptic Aβ hypothesis of Alzheimer disease

Nat. Neurosci.

Take five-BACE and the gamma-secretase quartet conduct Alzheimer’s amyloid beta-peptide generation

EMBO J.

ADAMs family members as amyloid precursor protein α-secretases

J. Neurosci. Res.

Secreted forms of beta-amyloid precursor protein modulate dendritic outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons

J. Neurobiol.

Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice

Proc. Natl. Acad. Sci. USA

Minireview
The amyloid precursor protein and postnatal neurogenesis/neuroregeneration