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Intraneuronal amyloid beta and reduced brain volume in a novel APP T714I mouse model for Alzheimer's disease.
Neurobiol Aging 2008; 29(2):241-52NA

Abstract

Transgenic mouse models of Alzheimer's disease (AD) expressing high levels of amyloid precursor protein (APP) with familial AD (FAD) mutations have proven to be extremely useful in understanding pathogenic processes of AD especially those that involve amyloidogenesis. We earlier described Austrian APP T714I pathology that leads to one of the earliest AD age-at-onsets with abundant intracellular and extracellular amyloid deposits in brain. The latter strikingly was non-fibrillar diffuse amyloid, composed of N-truncated A beta 42 in absence of A beta 40. In vitro, this mutation leads to one of the highest A beta 42/A beta 40 ratios among all FAD mutations. We generated an APP T714I transgenic mouse model that despite having 10 times lower transgene than endogenous murine APP deposited intraneuronal A beta in brain by 6 months of age. Accumulations increased with age, and this was paralleled by decreased brain sizes on volumetric MRI, compared to age-matched and similar transgene-expressing APP wild-type mice, although, with these levels of transgenic expression we did not detect neuronal loss or significant memory impairment. Immunohistochemical studies revealed that the majority of the intraneuronal A beta deposits colocalized with late endosomal markers, although some A beta inclusions were also positive for lysosomal and Golgi markers. These data support earlier observations of A beta accumulation in the endosomal-lysosomal pathway and the hypothesis that intraneuronal accumulation of A beta could be an important factor in the AD pathogenesis.

Authors+Show Affiliations

Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, BE-2610 Antwerpen, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17112635

Citation

Van Broeck, Bianca, et al. "Intraneuronal Amyloid Beta and Reduced Brain Volume in a Novel APP T714I Mouse Model for Alzheimer's Disease." Neurobiology of Aging, vol. 29, no. 2, 2008, pp. 241-52.
Van Broeck B, Vanhoutte G, Pirici D, et al. Intraneuronal amyloid beta and reduced brain volume in a novel APP T714I mouse model for Alzheimer's disease. Neurobiol Aging. 2008;29(2):241-52.
Van Broeck, B., Vanhoutte, G., Pirici, D., Van Dam, D., Wils, H., Cuijt, I., ... Kumar-Singh, S. (2008). Intraneuronal amyloid beta and reduced brain volume in a novel APP T714I mouse model for Alzheimer's disease. Neurobiology of Aging, 29(2), pp. 241-52.
Van Broeck B, et al. Intraneuronal Amyloid Beta and Reduced Brain Volume in a Novel APP T714I Mouse Model for Alzheimer's Disease. Neurobiol Aging. 2008;29(2):241-52. PubMed PMID: 17112635.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intraneuronal amyloid beta and reduced brain volume in a novel APP T714I mouse model for Alzheimer's disease. AU - Van Broeck,Bianca, AU - Vanhoutte,Greet, AU - Pirici,Daniel, AU - Van Dam,Debby, AU - Wils,Hans, AU - Cuijt,Ivy, AU - Vennekens,Krist'l, AU - Zabielski,Monika, AU - Michalik,Andrej, AU - Theuns,Jessie, AU - De Deyn,Peter Paul, AU - Van der Linden,Annemie, AU - Van Broeckhoven,Christine, AU - Kumar-Singh,Samir, Y1 - 2006/11/16/ PY - 2006/04/27/received PY - 2006/09/18/revised PY - 2006/10/04/accepted PY - 2006/11/23/pubmed PY - 2008/2/22/medline PY - 2006/11/23/entrez SP - 241 EP - 52 JF - Neurobiology of aging JO - Neurobiol. Aging VL - 29 IS - 2 N2 - Transgenic mouse models of Alzheimer's disease (AD) expressing high levels of amyloid precursor protein (APP) with familial AD (FAD) mutations have proven to be extremely useful in understanding pathogenic processes of AD especially those that involve amyloidogenesis. We earlier described Austrian APP T714I pathology that leads to one of the earliest AD age-at-onsets with abundant intracellular and extracellular amyloid deposits in brain. The latter strikingly was non-fibrillar diffuse amyloid, composed of N-truncated A beta 42 in absence of A beta 40. In vitro, this mutation leads to one of the highest A beta 42/A beta 40 ratios among all FAD mutations. We generated an APP T714I transgenic mouse model that despite having 10 times lower transgene than endogenous murine APP deposited intraneuronal A beta in brain by 6 months of age. Accumulations increased with age, and this was paralleled by decreased brain sizes on volumetric MRI, compared to age-matched and similar transgene-expressing APP wild-type mice, although, with these levels of transgenic expression we did not detect neuronal loss or significant memory impairment. Immunohistochemical studies revealed that the majority of the intraneuronal A beta deposits colocalized with late endosomal markers, although some A beta inclusions were also positive for lysosomal and Golgi markers. These data support earlier observations of A beta accumulation in the endosomal-lysosomal pathway and the hypothesis that intraneuronal accumulation of A beta could be an important factor in the AD pathogenesis. SN - 1558-1497 UR - https://www.unboundmedicine.com/medline/citation/17112635/Intraneuronal_amyloid_beta_and_reduced_brain_volume_in_a_novel_APP_T714I_mouse_model_for_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-4580(06)00358-7 DB - PRIME DP - Unbound Medicine ER -