Basic Science and Pathogenesis.

Background: Several genetic and cardiovascular risk factors increase incidence of Alzheimer's disease and related dementias (ADRD). Hypertension and the ε4 allele of apolipoprotein E (ApoE) are powerful drivers of cognitive impairment in ADRD. These risk factors are also associated with decreased cerebral blood flow (CBF).

Differential regulation of progranulin derived granulin peptides.

Background: Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome.

Alzheimer's disease and cerebrovascular pathology alter inward rectifier potassium (K 2.1) channels in endothelium of mouse cerebral arteries.

Background And Purpose: Inward rectifier potassium (K ) channels are key effectors of vasodilatation in neurovascular coupling (NVC). K channels expressed in cerebral endothelial cells (ECs) have been confirmed as essential modulators of NVC. Alzheimer's disease (AD) and cerebrovascular disease (CVD) impact on EC-K channel function, but whether oxidative stress or inflammation explains this impairment remains elusive.

A functional cerebral endothelium is necessary to protect against cognitive decline.

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included Nemo controls and three Nemo groups: One untreated, and two treated with simvastatin or exercise.

A Longitudinal Pilot Study on Cognition and Cerebral Hemodynamics in a Mouse Model of Preeclampsia Superimposed on Hypertension: Looking at Mothers and Their Offspring.

Preeclampsia is a common hypertensive disorder in pregnant women and whose causes and consequences have focused primarily on cardiovascular outcomes on the mother and offspring, often without taking into consideration the possible effects on the brain. One possible cause of preeclampsia has been attributed to alterations in the renin-angiotensin system, which has also been linked to cognitive decline. In this pilot study, we use a transgenic mouse model that chronically overexpresses human angiotensinogen and renin (RA mice) that displayed characteristics of preeclampsia such as proteinuria during gestation.

AT2R's (Angiotensin II Type 2 Receptor's) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease.

Antihypertensive medications targeting the renin-angiotensin system have lowered the incidence and progression of Alzheimer disease. Understanding how these medications function could lead to novel therapeutic strategies. AT4Rs (angiotensin IV receptors) have been associated with angiotensin receptor blockers' cognitive, cerebrovascular, and neuroinflammatory rescue in Alzheimer disease models.

Benefits of physical exercise on cognition and glial white matter pathology in a mouse model of vascular cognitive impairment and dementia.

White matter (WM) pathology is a clinically predictive feature of vascular cognitive impairment and dementia (VCID). Mice overexpressing transforming growth factor-β1 (TGF) with an underlying cerebrovascular pathology when fed a high cholesterol diet (HCD) develop cognitive deficits (VCID mice) that we recently found could be prevented by physical exercise (EX). Here, we further investigated cognitive and WM pathology in VCID mice and examined the cellular substrates of the protective effects of moderate aerobic EX focusing on WM alterations.

Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia.

Aerobic physical exercise (EX) and controlling cardiovascular risk factors in midlife can improve and protect cognitive function in healthy individuals and are considered to be effective at reducing late-onset dementia incidence. By investigating commonalities between these preventative approaches, we sought to identify possible targets for effective interventions. We compared the efficacy of EX and simvastatin (SV) pharmacotherapy to counteract cognitive deficits induced by a high-cholesterol diet (2%, HCD) in mice overexpressing TGF-β1 (TGF mice), a model of vascular cognitive impairment and dementia.

Spatial memory formation requires netrin-1 expression by neurons in the adult mammalian brain.

Netrin-1 was initially characterized as an axon guidance molecule that is essential for normal embryonic neural development; however, many types of neurons continue to express netrin-1 in the postnatal and adult mammalian brain. Netrin-1 and the netrin receptor DCC are both enriched at synapses. In the adult hippocampus, activity-dependent secretion of netrin-1 by neurons potentiates glutamatergic synapse function, and is critical for long-term potentiation, an experimental cellular model of learning and memory.

High cholesterol triggers white matter alterations and cognitive deficits in a mouse model of cerebrovascular disease: benefits of simvastatin.

Transgenic mice overexpressing transforming growth factor-β1 (TGF mice) display impaired cerebrovascular reactivity, cerebral hypoperfusion and neurovascular uncoupling, but no overt cognitive deficits until old age. Cardiovascular diseases are a major risk factor for vascular cognitive impairment and dementia (VCID). We investigated the impact of a high cholesterol diet (HCD) on cerebrovascular and cognitive function in adult (6 months) and aged (12 months) TGF mice, together with the potential benefit of simvastatin (SV), an anti-cholesterol drug with pleiotropic effects, in adult mice.

Pleiotropic Benefits of the Angiotensin Receptor Blocker Candesartan in a Mouse Model of Alzheimer Disease.

The angiotensin receptor blocker losartan mitigated cerebrovascular and cognitive deficits in mouse models of Alzheimer disease, in line with some clinical evidence of reduced onset and progression to Alzheimer disease. We investigated whether these benefits apply to another angiotensin receptor blocker, namely candesartan. Adult transgenic mice overexpressing a mutated form of the human APP (amyloid precursor protein) and wild-type controls were treated with vehicle or candesartan (cohort 1: 2 months, 1 mg/kg per day, osmotic subcutaneous minipumps; cohort 2: 5 months, 10 mg/kg per day in drinking water).

An endothelial link between the benefits of physical exercise in dementia.

The current absence of a disease-modifying treatment for Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) highlights the necessity for investigating the benefits of non-pharmacological approaches such as physical exercise (PE). Although evidence exists to support an association between regular PE and higher scores on cognitive function tests, and a slower rate of cognitive decline, there is no clear consensus on the underlying molecular mechanisms of the advantages of PE. This review seeks to summarize the positive effects of PE in human and animal studies while highlighting the vascular link between these benefits.

Circadian time-place (or time-route) learning in rats with hippocampal lesions.

Circadian time-place learning (TPL) is the ability to remember both the place and biological time of day that a significant event occurred (e.g., food availability).