Premium
O2‐02–01: Endogenous Aβ enhances memory retention in the rat
Author(s) -
Mathews Paul M.,
Garcia-Osta Ana,
Mazzella Matthew J.,
Alberini Cristina M.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.313
Subject(s) - hippocampus , amnesia , hippocampal formation , antibody , endogeny , in vivo , chemistry , inhibitory postsynaptic potential , memory consolidation , monoclonal antibody , saline , neuroscience , pharmacology , microbiology and biotechnology , biochemistry , endocrinology , biology , immunology , medicine , psychiatry
Background: The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the A peptides, which accumulate as -amyloid plaque in the brain during Alzheimer’s disease (AD). Synaptic activity has been shown to increase APP processing and A production, and it is generally believed that A , particularly A oligomers, have deleterious effects on synaptic function. Methods: We have examined the in vivo role of endogenous A in learning and memory consolidation by manipulating A levels in the hippocampus of rats using a newly generated anti-rodent A monoclonal antibody, antibody m3.2. Results: Antibody m3.2 recognizes non-denatured rodent A within residues 10-15, binds both rodent A 1-40 and A 1-42, and does not bind to human A . Bilateral hippocampal injections of 1 g of antibody m3.2 in 1 l isotonic saline before, but not after, training significantly disrupted inhibitory avoidance memory formation in rat. Injection of a control antibody had no effect. We co-injected human A 1-42 along with antibody m3.2 to determine whether exogenous A rescues the amnesia caused by antibody m3.2. Co-injection of 200 pM human A 1-42, which we determined by ELISA to be similar to the concentration of A 1-42 in the hippocampus of the rat, restored inhibitory avoidance memory formation. Furthermore, hippocampal administration of exogenous human A 1-42 at this physiological concentration without antibody m3.2 enhanced memory retention above baseline. Conclusions: Our findings suggest that A should not only be regarded as a synapto-toxic factor to be reduced in the CNS in order to avoid AD pathogenesis, but that it plays a critical role at physiological concentrations as a positive modulator of learning and/or an early phase of memory consolidation in the normal brain. Indeed, disruption or dysregulation of the normal function of A during AD pathogenesis may be one of the underlying causes of synaptic dysfunction in the disease. (Supported by the NINDS, NS045205, and the Alzheimer’s Association, IIRG-07-60047, to PMM; and by the NIMH, MH65635, to CMA.