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1.
Behav Brain Res ; 216(1): 77-83, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-20655336

ABSTRACT

Behavioural and psychological signs and symptoms of dementia encompass a wide range of neuropsychiatric disturbances which coincide with progressing cognitive decline in Alzheimer's disease (AD). Physical aggression and agitation, which occurs in 20-65% of AD patients, is physically and emotionally stressful, not only to patients but also to immediate family and caregivers. The exact mechanisms underlying the increased aggressive behaviour in AD has yet to be elucidated. We used a transgenic mouse model, denoted Tg2576, which over-expresses a mutated human amyloid precursor protein (APP) gene implicated in familial AD, to investigate aggressive behaviour of males at the stage of amyloid beta pathology preceding overt amyloid plaque deposition in the brain. The aggressive behaviour of transgenic and non-transgenic littermate males was evaluated in a standard resident-intruder test in which an isolated resident male responded aggressively toward an experimentally naïve intruder male of A/J strain. We showed that 7-month-old Tg2576 resident males demonstrated significantly higher and unchanged level of aggression towards intruder males during 3 consecutive encounters as compared to their non-transgenic littermate counterparts. These results validate further the Tg2576 mouse model of AD underscoring its usefulness in studying non-mnemonic changes in behaviour related to the disease.


Subject(s)
Aggression/physiology , Alzheimer Disease/genetics , Aggression/psychology , Alzheimer Disease/psychology , Analysis of Variance , Animals , Behavior, Animal/physiology , Disease Models, Animal , Male , Mice , Mice, Transgenic
2.
J Biol Chem ; 279(50): 52535-42, 2004 Dec 10.
Article in English | MEDLINE | ID: mdl-15452128

ABSTRACT

Amyloid-beta (Abeta) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by beta-secretase followed by gamma-secretase cleavage. Identification of the primary beta-secretase gene, BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Abeta metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating beta-secretase expression and activity alters APP processing and Abeta metabolism in vivo. Genomic-based BACE1 transgenic mice were generated that overexpress human BACE1 mRNA and protein. The highest expressing BACE1 transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing both BACE1 and APP show specific alterations in APP processing and age-dependent Abeta deposition. We observed elevated levels of Abeta isoforms as well as significant increases of Abeta deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for beta-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation of BACE1 activity may play a significant role in AD pathogenesis in vivo.


Subject(s)
Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Endopeptidases , Female , Gene Expression , Genomics , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Processing, Post-Translational , RNA, Messenger/genetics , RNA, Messenger/metabolism
3.
Neurobiol Dis ; 14(3): 619-23, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14678776

ABSTRACT

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is a rare autosomal dominant disorder caused by an amyloid-beta precursor protein (AbetaPP) 693 mutation that clinically leads to recurrent hemorrhagic strokes and dementia. The disease is pathologically characterised by the deposition of Abeta in cerebral blood vessels and as plaques in the brain parenchyma. This study measured the Abeta40 and Abeta42 concentration in plasma of Dutch AbetaPP693 mutation carriers and controls. We found that the Abeta40 concentration was not different between AbetaPP693 mutation carriers and controls. However, the Abeta42 concentration was significantly decreased in the mutation carriers. No correlation exists between the APOE(epsilon)4 allele and the plasma of Abeta40 and Abeta42 levels in HCHWA-D patients. This finding contrasted with the increased concentrations found in Alzheimer's disease. Therefore it is suggested that the Dutch AbetaPP693 mutation located within the Abeta coding region of the AbetaPP gene has a different effect not only on clinical and pathological expression but also on Abeta processing.


Subject(s)
Amyloid beta-Peptides/blood , Cerebral Amyloid Angiopathy, Familial/blood , Cerebral Amyloid Angiopathy, Familial/genetics , Down-Regulation/genetics , Peptide Fragments/blood , Adult , Aged , Apolipoprotein E4 , Apolipoproteins E/metabolism , Brain/blood supply , Brain/metabolism , Brain/pathology , Cerebral Arteries/metabolism , Cerebral Arteries/pathology , Cerebral Arteries/physiopathology , Female , Humans , Male , Middle Aged , Mutation/genetics
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