Role of Kalirin and mouse strain in retention of spatial memory training in an Alzheimer’s disease model mouse line

Alzheimer’s Disease is highly age-dependent, and although initially considered a human only disease, several experimental animal systems have shown human-like age-dependent symptoms like loss of coordination, Type II diabetes, hearing and vision degradation, slow movement, and loss of coordination. However, the associated cortical tissue losses, intracellular phosphorylated Tau tangles, and deposition of extracellular beta amyloid plaques are unique to humans. A better understanding of the pathophysiology of Alzheimer’s disease would therefore be desirable to bring the innumerable failed therapeutic trials to a successful closure.

3xTG mice and 5xFAD mice are the most widely used transgenic animal Alzheimer’s disease models, and like other models, they incorporate Alzheimer’s disease-associated humanized mutant amyloid precursor protein (APP), mutations in presenilin 1 (PSEN1), and mutant human TAU. 3xTG mice have humanized TAU with a single mutation, a transgene encoding humanized mutant amyloid precursor protein, and a knock-in activating mutation into endogenous mouse presenilin. 5xFAD mice, on the other hand, harbor 2 Thy1-promoter-driven plasmids expressing APP and PSEN1 with a total of 5 mutations observed in various cases of familial Alzheimer’s disease. These animal disease models have been an essential research tool in drug discovery and development to find therapeutic candidates for Alzheimer’s disease.

A number of genetic studies have implicated altered Kalirin expression in a variety of brain disorders such as schizophrenia and Alzheimer’s Disease. Kalirin is a regulator of the number and functionality of dendritic spines. When neurons are progressively exposed to amyloid precursor protein, their dendrites begin to lose their spines, and Kal7, the most abundant Kalirin isoform in the human brain is also lost. Kal7 proteins have been observed to substantially decline in postmortem Alzheimer’s disease cortical extracts, and in late-stage human Alzheimer’s disease, KALRN mRNA declines substantially, but has been observed not to decline in healthy individuals.

University of Connecticut researchers: Lillian Russo-Savage (currently a graduate student at the University of Vermont), Dr. Vishwanatha Rao, Professor Betty Eipper, and Professor Richard Mains, in a bid to evaluate the possible synergism of Kalirin loss with the presence of mutant humanized amyloid precursor protein, hTAU, and presenilin 1 (PSEN1), examined mice from the mating of the 3xTG mice with Kalirin knockout mice. The study aimed to investigate whether Kalirin deficits could exacerbate deficits in 3xTG mice. The original research article is currently published in the journal, Neurobiology of Aging.

In their studies, 3xTG transgenic and nontransgenic mice, both of which express mutant human amyloid precursor protein (hAPP) together with Alzheimer’s disease-associated forms of presenilin and hTau were equivalently put under the Barnes Maze escape task between the ages of 3-9 months. To check if Kalirin could worsen deficits in the 3xTG mice, 3xTG mice with only one functional Kalirin allele were also generated.

The researchers found that non-transgenic control mice and naïve homozygous 3xTG mice showed remarkable results when tested for spatial memory acquisition at 3, 6 and again at 9 months of age under the Barnes Maze task. After nine months, the nontransgenic mice still had the memory of the Barnes Maze task done three and six months earlier. It was the same case for mice with a single functional Kalirin allele. In contrast, when tested at six or nine months of age, prior training didn’t produce any improvement in the performance of hemizygous and homozygous 3xTG-AD mice.

The authors observed that Kalirin expression was highly age- and sex-dependent in C57 mice but not in the other mouse strain (B6129) tested. In contrast, human amyloid precursor protein (hAPP) levels in the 3xTG mice were observed to increase amyloid precursor protein levels at all ages. Therefore, although seen as a prime contributor to Alzheimer’s disease symptoms, inactivation of a single Kalirin allele didn’t impose any effect on 3X-TG-AD and C57 mice Barnes Maze performance.

The findings of the study should aid in using the most appropriate mouse strain in the elucidation of Kalirin’s role in Alzheimer’s disease and in the identification of new therapeutic approaches.