Currently, it is controversially discussed whether a relationship between obesity and cognition exists. We here analyzed a mouse model of obesity (leptin-deficient mice) to study the effects of obesity on the morphology of the hippocampus (a brain structure involved in mechanisms related to learning and memory) and on behavior. Mice aged 4 to 6 months were analyzed. At this age, the obese mice have nearly double the body weight as controls, but display smaller brains (brain volume is about 10% smaller) as control animals of the same age. Adult hippocampal neurogenesis, a process that is linked to learning and memory, might be disturbed in the obese mice and contribute to the smaller brain volume. Adult hippocampal neurogenesis was examined using specific markers for cell proliferation (phosphohistone H3), neuronal differentiation (doublecortin), and apoptosis (caspase 3). The number of phosphohistone H3 and doublecortin-positive cells was markedly reduced in leptin-deficient mice, but not the number of apoptotic cells, indicating that adult hippocampal neurogenesis on the level of cell proliferation was affected. In addition, dendritic spine densities of pyramidal neurons in the hippocampal area CA1 were analyzed using Golgi impregnation. However, no significant change in dendritic spine densities was noted in the obese mice. Moreover, the performance of the mice was analyzed in the open field as well as in the Morris water maze. In the open field test, obese mice showed reduced locomotor activity, but in the Morris water maze they showed similar performance compared with control animals.

Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for <1% of all patients with Alzheimer's disease. The inherited form is even regarded a 'rare' disease according to the regulations for funding of the European Union (www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-β-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-β clearance from the brain, develop various aspects of sporadic Alzheimer's disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows investigations without artificial overexpression of inherited Alzheimer's disease genes.

The (pro)renin receptor [(P)RR], also known as ATP6AP2 [ATPase 6 accessory protein 2], is highly expressed in the brain. ATP6AP2 plays a role in early brain development, adult hippocampal neurogenesis and in cognitive functions. Lack of ATP6AP2 has deleterious effects, and mutations of ATP6AP2 in humans are associated with, e.g. X-linked intellectual disability. However, little is known about the effects of over-expression of ATP6AP2 in the adult brain. We hypothesized that mice over-expressing ATP6AP2 in the brain might exhibit altered neuroanatomical features and behavioural responses. To this end, we investigated heterozygous transgenic female mice and confirmed increased levels of ATP6AP2 in the brain. Our data show that over-expression of ATP6AP2 does not affect adult hippocampal neurogenesis, exercise-induced cell proliferation, or dendritic spine densities in the hippocampus. Only a reduced ventricular volume on the gross morphological level was found. However, ATP6AP2 over-expressing mice displayed altered exploratory behaviour with respect to the hole-board and novel object recognition tests. Moreover, primary adult hippocampal neural stem cells over-expressing ATP6AP2 exhibit a faster cell cycle progression and increased cell proliferation. Together, in contrast to the known deleterious effects of ATP6AP2 depletion, a moderate over-expression results in moderate behavioural changes and affects cell proliferation rate in vitro.

On the one hand, the emotional state can influence food intake and on the other hand, hunger can have an impact on the emotional state. Leptin, which is encoded by the ob gene, is involved in the energy homeostasis and plays a role in development of obesity. Mice deficient for leptin (ob/ob) are obese and display several behavioral alterations. It has been shown that ob/ob mice display striking changes in neuronal plasticity within the limbic system, e.g., hippocampal formation. We focus on alterations in ob/ob mice that can be related to alter processing in another part of the limbic system, the amygdala. ob/ob mice have a higher food consumption than age-matched controls, which might have an impact on the emotional state of these mice. Since the amygdala is involved in emotional processing, we analyze whether ob/ob mice display alterations in plasticity at the electrophysiological and structural level. No changes were seen in dendritic spine densities in the basolateral and lateral (LA) nucleus of the amygdala. Interestingly and in contrast to the hippocampus (Porter et al. 2013), long-term potentiation in the LA was increased in ob/ob mice. Our results indicate that amygdalar and hippocampal synaptic plasticity are regulated in different ways by leptin deficiency in accordance with the different functions of these limbic structures in stress and anxiety.

The classical renin-angiotensin system (RAS) in the body has been studied intensively in the last decades, since it is known that this system is involved in the regulation of blood pressure. Since nearly all members of the classical RAS have also been identified within the brain in the last decades and due to the existence of the blood-brain barrier, a RAS within the brain (bRAS) that is largely independent from the peripheral RAS has been postulated. All members of the angiotensin family as e.g., angiotensin II, angiotensin IV and angiotensin II (1–7) along with the respective receptors (e.g., angiotensin II receptor type 1 (AT1), angiotensin II receptor type 2 (AT2), angiotensin IV receptor (AT4), angiotensin II (1–7) receptor (Mas)) have been identified within the brain. Moreover, a receptor capable of binding renin and the renin precursor prorenin with high affinity has also been detected within the brain. This protein functions as a membrane receptor for (pro)renin and also represents a V-ATPase subunit and is therefore termed (P)RR or Atp6ap2, respectively. In this review we shed light on the (known as well as putative) roles and functions of Atp6ap2 in the brain under physiological and pathophysiological conditions.