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General Information
Name
Alzheimer disease 1
FlyBase ID
FBhh0000119
Disease Ontology Term
Parent Disease
Overview

This report describes Alzheimer disease 1 (AD1), which is a subtype of Alzheimer disease; AD1 is inherited as an autosomal dominant. The human gene implicated in this disease is APP, amyloid beta A4 precursor protein. Peptides derived from APP are the major component of amyloid plaques found in the brains of Alzheimer patients; the most common of these is amyloidβ42 (Aβ42). The human APP gene is also implicated in a second disease, cerebral amyloid angiopathy, APP-related (OMIM:605714; FBhh0000544). There is a single fly ortholog of APP, Dmel\Appl, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Appl is orthologous to two additional human genes, APLP1 and APLP2, neither of which is implicated in human disease.

Multiple different UAS constructs of the human Hsap\APP gene have been introduced into flies, expressing the wild-type protein, the APP protein with introduced modification, or a subset of APP peptides. Some Alzheimer disease models use Hsap\APP in combination with other genes thought to impact the disease, such as Hsap\BACE1 (FBhh0000580) and Hsap\MAPT (FBhh0000101). Phenotypic assays using the human gene have allowed characterization of genetic interactions with numerous other genes.

Variant(s) implicated in human disease tested (as transgenic human gene, APP): K670N.M671L (affects 2 adjacent amino acids; designated Hsap\APP695-Swedish.UAS) and V717F variant forms of the human gene have been introduced into flies. A double mutant, K670N.M671L plus E693G, has been introduced into flies and is available, but has not been characterized.

Variant(s) implicated in human disease tested (as transgenic human amyloid peptide, Aβ42): the E693G (E22G in the amyloid peptide; see alleles designated Hsap\APP[Arctic.xxx]), D671_E673delinsQ (D1_E3delinsQ in the amyloid peptide), and S679D (S8D in the amyloid peptide) variant forms have been introduced into flies. The variant A692G (A21G) has been introduced into flies and is available, but has not been characterized.

Variants of APP associated with cerebral amyloid angiopathy have been introduced into flies and are available, but have not been characterized. See the disease report for cerebral amyloid angiopathy, APP-related (FBhh0000544).

Animals homozygous for a loss-of-function mutation in the Dmel\Appl gene exhibit learning and memory defects and neuroanatomy defective phenotypes. Physical interactions of the Dmel\Appl protein product have been described; see below and in the FlyBase gene report for Dmel\Appl. Phenotypic assays using the fly gene have allowed characterization of genetic interactions.

[updated Mar. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: Alzheimer disease
Symptoms and phenotype

Alzheimer disease (AD) is the most common form of progressive dementia in the elderly. [from OMIM:104300; 2016.01.08]

Memory loss is the most common sign of Alzheimer disease. As the disorder progresses, some people with AD experience personality and behavioral changes; other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. Total care is usually required during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]

Alzheimer disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear before age 65, while the late-onset form appears after age 65. The early-onset form is much less common than the late-onset form, accounting for less than 5 percent of all cases of Alzheimer disease. [from Genetics Home Reference, Alzheimer disease; 2016.01.08]

Specific Disease Summary: Alzheimer disease 1
OMIM report

[ALZHEIMER DISEASE; AD](https://omim.org/entry/104300)

Human gene(s) implicated

[HOMEOSTATIC IRON REGULATOR; HFE](https://omim.org/entry/613609)

[NITRIC OXIDE SYNTHASE 3; NOS3](https://omim.org/entry/163729)

[PLASMINOGEN ACTIVATOR, URINARY; PLAU](https://omim.org/entry/191840)

[ALPHA-2-MACROGLOBULIN; A2M](https://omim.org/entry/103950)

[MYELOPEROXIDASE; MPO](https://omim.org/entry/606989)

[AMYLOID BETA A4 PRECURSOR PROTEIN; APP](https://omim.org/entry/104760)

Symptoms and phenotype

Alzheimer disease 1 (AD1) is characterized by typical symptoms of Alzheimer disease (described above).

Genetics

Alzheimer disease 1 is inherited as an autosomal dominant; it is associated with heterozygous mutations in the APP gene [from OMIM:104300; 2016.01.08]

Cellular phenotype and pathology
Molecular information

Peptides derived from the amyloid beta A4 precursor protein (APP) are the major component of amyloid plaques found in the brains of Alzheimer patients. [from OMIM:104760; 2016.01.08]

External links
Disease synonyms
AD1
Alzheimer disease 1, familial
Alzheimer disease, early-onset
early-onset familial Alzheimer disease
eFAD
EOFAD
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila. Three human genes, APP, APLP2 and APLP1, are orthologous to the fly gene Dmel\Appl.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    In progress.Contributions welcome.
    Gene Groups / Pathways
      Comments on ortholog(s)

      Ortholog of human APP (reciprocal best hit), APLP2 and APLP1 (1 Drosophila to 3 human). Dmel\Appl shares 23-25% identity and 36-42% similarity with the 3 human genes.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (11 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, anti tag western blot, two hybrid, anti tag coimmunoprecipitation, western blot, pull down
      pull down, autoradiography
      experimental knowledge based
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      experimental knowledge based
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, western blot, pull down, anti tag western blot, two hybrid
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (69 alleles)
      Models Based on Experimental Evidence ( 6 )
      Modifiers Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 63 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 18 )
      Allele
      Disease
      Interaction
      References
      is exacerbated by mir-282EP3041
      is ameliorated by CG2924EP1596
      is exacerbated by CG7231EP2510
      is exacerbated by svrKG02090
      is exacerbated by elB9
      is exacerbated by Nep2KG05754
      is exacerbated by SNF4AγKG10152
      is exacerbated by ATP7EY07895
      is exacerbated by cwoEP3470
      is exacerbated by Sin3A08269
      is exacerbated by SNF4AγEP3015b
      is exacerbated by elBEP965
      is exacerbated by mubEP3108
      is ameliorated by gEP514
      is exacerbated by HDAC104556
      is exacerbated by HDAC4KG09091
      is exacerbated by PrpsKG00420
      is exacerbated by Sap130EY12079
      is exacerbated by TlEP1051
      is exacerbated by esgEP684
      is ameliorated by gB166
      is exacerbated by svr126
      is exacerbated by svrEP356
      is exacerbated by Dsp1EP355
      is ameliorated by CG6175EP3405
      is exacerbated by MESR4EP386
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      loss of function allele
      gamma ray
      References (270)