Delayed behavioral effects following intrahippocampal injection of aggregated A beta (1-42).
Beta amyloid protein (A beta) is the major extracellular component of Alzheimer's disease (AD) plaques. In the current study, A beta (1-42) was aggregated in vitro using a method which produces A beta aggregates similar to those found in the AD brain. Twelve male Sprague-Dawley rats were trained in two-lever operant chambers under an alternating lever cyclic-ratio (ALCR) schedule. When performance was stable on the ALCR schedule, six subjects were injected (bilaterally into the CA3 area of the dorsal hippocampus) with 5.0 microliters aggregated A beta in suspension, and the remaining six subjects were injected with 5.0 microliters sterile water. Behavioral testing resumed 5 days after surgery and continued for 90 days post-injection. Aggregated A beta injection did not affect the number of lever switching errors made in a daily session but did affect the number of incorrect lever response perseverations. After approximately 30 days post-injection, aggregated A beta injection detrimentally affected ability to track the changing parameters of the schedule, and decreased the efficiency by which subjects obtained reinforcers. From approximately day 50 post-injection onward, A beta-injected subjects demonstrated significantly higher numbers of incorrect lever response perseverations than did sterile water-injected subjects. These effects appeared to be central rather than peripheral, as A beta injection did not decrease running response rates under the ALCR schedule. The delayed onset of behavioral effects seen in this and other behavioral studies may be a result of a cascade of potentially harmful responses induced through glial activation following aggregated A beta injection.
O'Hare
E
E
Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
Weldon
D T
DT
Mantyh
P W
PW
Ghilardi
J R
JR
Finke
M P
MP
Kuskowski
M A
MA
Maggio
J E
JE
Shephard
R A
RA
Cleary
J
J
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D008845:Microinjections; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors