Increased expression of hippocampal cholinergic neurostimulating peptide-related components and their messenger RNAs in the hippocampus of aged senescence-accelerated mice.
Hippocampal cholinergic neurostimulating peptide stimulates cholinergic phenotype development by inducing choline acetyltransferase in the rat medial septal nucleus in vitro. Adult senescence-accelerated-prone mice/8, a substrain of the senescence-accelerated-prone mouse, show a remarkable age-accelerated deterioration in learning and memory. We cloned mouse hippocampal cholinergic neurostimulating peptide precursor protein complementary DNA. The deduced amino acid sequence showed that the neurostimulating peptide itself is the same as that found in the rat. In situ hybridization revealed that the highest expression of the precursor protein messenger RNA was in hippocampal pyramidal neurons. Compared with a strain of senescence-accelerated-resistant mouse (control mouse), adult senescence-accelerated-prone mice/8 showed increased expression of both the precursor messenger RNA and the neurostimulating peptide-related immunodeposits in the hippocampal CA1 field. The deposits were intensely and diffusely precipitated in neuropils throughout the strata oriens and radiatum in senescence-accelerated-prone mice/8, but not in control mice. The neurostimulating peptide content in the hippocampus was higher in senescence-accelerated-prone mice/8 than in control mice, while its precursor protein itself was not different between the two strains. Furthermore, our previous and present data show that the medial septal and hippocampal choline acetyltransferase activity was significantly lower in senescence-accelerated-prone mice/8 than in control mice. The data suggest that, in hippocampal neurons in adult senescence-accelerated-prone mice/8, the production of hippocampal cholinergic neurostimulating peptide precursor protein in neuronal somata, which is associated with an increased expression of its messenger RNA in the CA1 field, occurs as a consequence of low activity in their presynaptic cholinergic neurons. This is followed by accelerated processing to generate bioactive peptide and transport to its functional fields. However, certain mechanisms reduce the release of the peptide and lead to its accumulation in the neuropil. These disturbances of the septohippocampal cholinergic system might be the biochemical mechanism underlying the characteristic deterioration of senescence-accelerated-prone mice/8.
Second Department of Internal Medicine, Medical School, Nagoya City University, Nagoya, Japan.
N
N
Matsukawa
I
I
Tooyama
H
H
Kimura
T
T
Yamamoto
Y
Y
Tsugu
Y
Y
Oomura
K
K
Ojika
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002795:Choline O-Acetyltransferase / Q000235:genetics; D018678:Cholinergic Agents; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
D018678:Cholinergic Agents; D009479:Neuropeptides; D012333:RNA, Messenger; D011994:Recombinant Proteins; C075274:hippocampal cholinergic neurostimulating peptide; D002795:Choline O-Acetyltransferase