Function

Amyloid precursor protein [APP] is endoproteolytically processed by BACE1 and gamma-secretase to release amyloid peptides [Abeta40 and 42] that aggregate to form senile plaques in the brains of patients with Alzheimer's disease [AD]. The C-terminus of Abeta40/42 is generated by gamma-secretase, whose activity is dependent upon presenilin 1 and presenilin 2 [PS 1 or 2].

Pathology

 germline mutations in Alzheimer disease

• in familial Alzheimer disease
• in early-onset Alzheimer disease
• in late-onset Alzheimer disease

 duplication of the APP locus on chromosome 21 in autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA)

• Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides.
• Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA.

 germline mutations in dutch type cerebroarterial amyloidosis (cerebral amyloid angiopathies)

• in dutch type cerebroarterial amyloidosis with presenile dementia
• in artic type cerebroarterial amyloidosis
• in italian type cerebroarterial amyloidosis
• in Iowa type cerebroarterial amyloidosis

 germline mutations in the familial occipital calcifications, hemorrhagic strokes, leukoencephalopathy, arterial dysplasia, and dementia (FOCCHS-LADD) syndrome (MIM.605714)

 variant in chronic schizophrenic with cognitive defects

References

References

 Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan;38(1):24-6. PMID: #16369530#

 Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol. 2003 Sep;62(9):885-98. PMID: #14533778#

 Vardy ER, Catto AJ, Hooper NM. Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer's disease. Trends Mol Med. 2005 Oct;11(10):464-72. PMID: #16153892#

 Laferla FM, Oddo S. Alzheimer's disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. PMID: #15823755#

 Nixon RA. Niemann-Pick Type C disease and Alzheimer's disease: the APP-endosome connection fattens up. Am J Pathol. 2004 Mar;164(3):757-61. PMID: #14982829#