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PubMed: 27522251

Title
A role for β2* nicotinic receptors in a model of local amyloid pathology induced in dentate gyrus.
Journal
Neurobiology of aging
Volume
46
Issue
None
Pages
221-34
Date
2016-10-01
Authors
Catteau J | Besson M | Lombardo S | Maskos U

Evidence f98757ebf4
JSON

We did not detect any glia or microglia activation in WT-APP (Fig. 3C and F) compared with WT-GFP (Fig. 3B and E), meaning that the neuroinflammation does not play a role in the memory deficit we observed

bp(GO:"inflammatory response") causesNoChange path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) causesNoChange bp(GO:"microglial cell activation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) causesNoChange act(a(MESH:Neuroglia)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 30db702c86
JSON

However, we identify a possible role of the alpha7 subunit in the normal aging process that should be further investigated

bp(GO:aging) association p(MGI:Chrna7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

p(MGI:Chrna7) association bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 19f3c05278
JSON

The hAPP-SLA transduction in DG did not induce a memory deficit in beta2 KO, meaning that the Abeta/beta2-nAChR interaction is required to drive the memory deficit in this model

complex(a(CHEBI:"amyloid-beta"), p(FPLX:CHRN)) increases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

complex(a(CHEBI:"amyloid-beta"), p(MGI:Chrnb2)) increases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 889d6c7cce
JSON

In the NPR task (7 months p.i.), the GFP-beta2 spent significantly more time exploring the novel compartment (p = 0.003; Fig. 4A), as well as APP-beta2 (p = 0.017; Fig. 4B).

p(MGI:Chrnb2) decreases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

composite(p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")), p(MGI:Chrnb2)) decreases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 1d58292d61
JSON

We observed intracellular Abeta staining in the polymorphic layer of the DG that was absent in GFP-beta2 (Fig. 8)

p(MGI:Chrnb2) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 3a3c01cdaf
JSON

At 7 months p.i., both GFP-alpha7 (p = 0.9; Fig. 5A) and APP-alpha7 groups (p = 0.3; Fig. 5B) displayed a memory deficit in the NPR task.

composite(p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")), p(MGI:Chrna7)) decreases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 17c202c885
JSON

The analysis of the total exploration time during the NOR task showed that GFP-alpha7 spent similar time exploring the familiar and the novel objects (p = 0.76; Fig. 5D), whereas APP-alpha7 spent significantly more time exploring the novel object compared with the familiar one (p = 0.01; Fig. 5E)

composite(p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")), p(MGI:Chrna7)) decreases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence ae44e75b24
JSON

In the NOR task (15 months p.i.) as well, both GFP-alpha7 and APP-alpha7 displayed a cognitive impairment (Fig. 5DeE)

composite(p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")), p(MGI:Chrna7)) decreases path(MESH:"Cognitive Dysfunction") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

p(MGI:Chrna7) decreases path(MESH:"Cognitive Dysfunction") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence eb83194a03
JSON

Immunofluorescence performed with VHH 31-1 on brain slices of APP-alpha7 mice also showed intracellular Abeta oligomers in the polymorphic layer (Fig. 8, arrows), whereas GFP-alpha7 mice did not show any Abeta oligomers

composite(p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")), p(MGI:Chrna7)) decreases a(HBP:HBP00022) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

p(MGI:Chrna7) increases a(HBP:HBP00022) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 120826bf48
JSON

However, the analysis of the recognition percentage for the same set of data showed that GFP-WT spent significantly more time exploring the novel object compared with APP-WT (p = 0.0032; Fig. 2E), suggesting the presence of a memory deficit in the APP-WT group.

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) increases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence af3da9af52
JSON

Hence, the transduction of hAPP-SLA in DG induces recognition memory deficits as supported by NPR and NOR tasks

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) increases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 86ac8c31c9
JSON

Similarly, in the NOR task (15 months p.i.), both the GFP-beta2 and the APP-beta2 displayed higher exploration of the novel object (p < 0.0001 and p = 0.0001, respectively; Fig. 4C and D), with no differences between the 2 groups in the recognition index (p = 0.7; Fig. 4E), meaning that beta2 mice injected with hAPP-SLA did not exhibit the recognition memory deficit observed in APP-WT

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) increases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

composite(p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")), p(MGI:Chrnb2)) decreases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence e764117db1
JSON

The locomotor behavior during the NOR habituation phase was measured by the total distance traveled: APP-WT showed higher locomotor activity compared with GFP-WT (p = 0.0027; Fig. 2F)

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) increases bp(GO:locomotion) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence a0dc63e105
JSON

We finally measured anxiety levels using the LDB paradigm. No differences were observed between both groups for the index of time spent in the lit compartment (p = 0.7) as well as for the number of transitions (p = 0.2; Fig. 2GeH)

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) causesNoChange path(MESH:Anxiety) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence b09434795a
JSON

In addition, viral transduction did not induce any neuroinflammation, as shown in WT noninjected mice (Fig. 3A and D)

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) causesNoChange bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence a6b2be548d
JSON

The presence of oligomeric Abeta in APP-WT was confirmed with the antibody VHH 31-1, specific for oligomeric forms of Abeta (Lafaye et al., 2009)

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) increases a(HBP:HBP00022) View Subject | View Object

Appears in Networks:

Evidence bfd46e277e
JSON

Abeta was mainly found in the polymorphic layer of the DG (Fig. 6, arrows)

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) increases a(HBP:HBP00022) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 2e14e4f67b
JSON

Abeta intracellular accumulation in DG polymorphic layer was also confirmed with the rat monoclonal 7H3D6 antibody, also specific for oligomeric Abeta (Kumar et al., 2013) (Fig. 7, arrow)

p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")) increases a(HBP:HBP00022) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence d091cfe519
JSON

Noninjected mice spent the same amount of time exploring novel and familiar compartments during the test session (p = 0.6; Fig. 5C), confirming the presence of a constitutive recognition memory deficit in age-matched alpha7 KO mice

p(MGI:Chrna7) decreases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 835cddd275
JSON

Because the alpha7 KO had a memory deficit independent of hAPP-SLA expression, we could not draw any conclusion on the role of alpha7 in the memory deficit observed

p(MGI:Chrna7) decreases path(MESH:"Memory Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dentate Gyrus

Evidence 9faf1b31fd
JSON

We then investigated the presence of Abeta aggregates in the hippocampus of APP-beta2 and APP-alpha7. In APP-beta2, a positive staining for Abeta oligomers using the VHH 31-1 antibody was found (Fig. 8, arrows)

composite(p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu"), var("p.Thr714Ile"), var("p.Val717Ile")), p(MGI:Chrnb2)) decreases a(HBP:HBP00022) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 7df3c8832c
JSON

Several studies showed that in AD animal models, the appearance of the cognitive deficits precedes plaque deposition (Casas et al., 2004; Gouras et al., 2000; Kumar et al., 2013; Wirths et al., 2004)

path(MESH:"Alzheimer Disease") increases path(MESH:"Cognitive Dysfunction") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Cognitive Dysfunction") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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