A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease

Abstract

Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive beta-amyloid plaque formation that the hAPP mice display is puzzling. In the water maze, hAPP mice are impaired before and after amyloid plaque deposition. Here we show, using a new water-maze training protocol, that PDAPP mice also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with beta-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that A beta overexpression and/or A beta plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

“…These mice develop early synaptic deficits 12 and several neuropathological features at older age, including amyloid plaques and dystrophic neurites 13 . Although Tg2576 mice lack neurofibrillary tangles and significant neuronal loss 14 , there is strong evidence that accumulation of the amyloid-β (Aβ) peptide, derived via APP proteolysis, is responsible for age-related memory decline in this model [15][16][17] .…”

“…These mice develop early synaptic deficits 12 and several neuropathological features at older age, including amyloid plaques and dystrophic neurites 13 . Although Tg2576 mice lack neurofibrillary tangles and significant neuronal loss 14 , there is strong evidence that accumulation of the amyloid-β (Aβ) peptide, derived via APP proteolysis, is responsible for age-related memory decline in this model [15][16][17] .By means of several experimental approaches, we demonstrate an increase of caspase-3 activity in Tg2576 hippocampal synapses at 3 months of age, much earlier than amyloid plaque deposition is detectable 11 . We report that this enhanced local caspase-3 activity leads to a permanent activation of calcineurin which causes, in turn, AMPA receptor (AMPAR) GluR1 subunit dephosphorylation and its removal from the post-synaptic sites.…”

Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch

“…Briefly, the N-terminus of the immunodominant B cell epitope of Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] was synthesized in tandem with a promiscuous foreign T cell epitope, PADRE (aK-Cha-VAAWTLKAAa, where "a" is D alanine and "Cha" is L-cyclohexylalanine) as Multiple Antigenic Peptides (MAP), which contain a core matrix of 4 branching lysines [42,43] to generate PADRE-Aβ 1-15 -MAP molecules (Invitrogen Inc., CA).…”

“…One potentially powerful strategy for reducing the level of Aβ in the brain is immunotherapy, in which antibodies specific to Aβ facilitate the clearance of amyloid deposits [10][11][12][13][14][15][16][17][18]. The first human AD vaccine consisted of fibrillar Aβ 42 formulated in QS21 adjuvant (AN-1792 trial) that induced strong Th1-type anti-Aβ immune responses [19], even in Th2-prone BALB/c mice [20].…”

“…In the present study, we compared the immunogenicity of our novel prototype epitope vaccine that contains the immunodominant B cell epitope of Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] in tandem with the synthetic universal helper T cell epitope, PADRE (PADRE-Aβ 1-15 -MAP) [36] formulated in Th1-type adjuvant (Quil A) or Th2-type adjuvant (Alum). To identify an acceptable adjuvant formulation for use in future pre-clinical and clinical trials, we tested the use of different combinations of Quil A and Alum in BALB/c and C57BL/6 mice of two different haplotypes H-2 d and H-2 b , respectively.…”