Medial septal beta-amyloid 1-40 injections alter septo-hippocampal anatomy and function.

Degeneration of septal neurons in Alzheimer's disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum modulates the activity of hippocampal and cortical circuits and is crucial to the initiation and occurrence of oscillatory activities such as the hippocampal theta rhythm. Previous studies suggest that amyloid beta peptide (Abeta) accumulation may trigger degeneration in AD. This study evaluates the effects of single injections of Abeta 1-40 into the medial septum. Immunohistochemistry revealed a decrease in septal cholinergic (57%) and glutamatergic (53%) neurons in Abeta 1-40 treated tissue. Additionally, glutamatergic terminals were significantly less in Abeta treated tissue. In contrast, septal GABAergic neurons were spared. Unitary recordings from septal neurons and hippocampal field potentials revealed an approximately 50% increase in firing rates of slow firing septal neurons during theta rhythm and large irregular amplitude (LIA) hippocampal activities and a significantly reduced hippocampal theta rhythm power (49%) in Abeta 1-40 treated tissue. Abeta also markedly reduced the proportion of slow firing septal neurons correlated to the hippocampal theta rhythm by 96%. These results confirm that Abeta alters the anatomy and physiology of the medial septum contributing to septo-hippocampal dysfunction. The Abeta induced injury of septal cholinergic and glutamatergic networks may contribute to an altered hippocampal theta rhythm which may underlie the memory loss typically observed in AD patients.

Abnormalities and reduced reproductive potential of sperm from Tnp1- and Tnp2-null double mutant mice.

Previous studies have demonstrated the importance of transition nuclear proteins, TP1 and TP2, in spermatogenesis and male fertility. However, importance of the overall level of transition proteins and their level of redundancy in the production of normal sperm is not clear. Epididymal sperm from the nine possible Tnp1 and Tnp2 null genotypes demonstrated a general decrease in normal morphology, motility, chromatin condensation, and degree of protamine 2 processing with decreasing levels of transition proteins in mutant sperm. Nuclei of some mutant epididymal sperm stained poorly with hematoxylin and DNA fluorochromes, suggesting that the DNA of these sperm underwent degradation during epididymal transport. When epididymal sperm were injected directly into oocytes, fertilization and embryonic development were reduced only in the two most severely affected genotypes. These phenotypes indicated some functional redundancy of transition proteins; however, redundancy of transition protein function was not complete, as, for example, sperm from double heterozygous males had fewer abnormalities than sperm from males homozygous for a single Tnp null mutation. Our study suggests that each TP fulfills some unique function during spermiogenesis even though sperm phenotypes strongly indicate defects are largely attributable to an overall gene dosage effect. Similarities between sperm defects found in Tnp mutants and infertile patients make the Tnp mutants a valuable tool with which to study outcomes following fertilization using sperm with compromised DNA integrity.

Nucleoprotein transitions during spermiogenesis in mice with transition nuclear protein Tnp1 and Tnp2 mutations.

Chromatin remodeling during spermiogenesis is characterized by a series of nuclear protein replacements. Histones are replaced by transition nuclear proteins, which are in turn replaced by protamines. The transition nuclear proteins, TP1 and TP2, and the protamines, PRM1 and PRM2, are the major nuclear proteins involved in this process. Biochemical studies of mice with null mutations in one of the Tnp genes showed that the absence of one TP led to an apparent elevation in the amount of the remaining TP in the testis. To investigate the mechanism of changes of protein levels and effects of one Tnp mutation on other nuclear proteins, we used immunohistochemistry techniques to determine the distribution of these nuclear proteins. In contrast to previous biochemical analyses, which indicated that nuclear protein replacement was sequential with little overlap between the protein types, we found considerable overlap in the nucleoprotein types during spermiogenesis. The TPs, which appear in the nucleus before histone displacement is complete, were shared among genetically inequivalent spermatids. The absence of one TP did not affect the time of appearance of the other TP or of the protamines, but it did affect the displacement of the other TP, leading to its abnormal retention in the nucleus. The elevated levels of the remaining TP in Tnp-mutant mice appeared to be a consequence of the prolonged retention, rather than increased synthesis. Thus the absence of one of the TPs did not significantly affect transcription or translation of the other basic proteins, but it did affect posttranslational events.