The burning brain: neuroinflammation as an early phenomenon linking Alzheimer’s disease and depression

Dementia, also known as Major Neurocognitive Disorder (MND), is an umbrella term for a collection of symptoms impacting on memory, behaviour, thinking and social abilities. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which affects 50-60% of people with dementia, being the most common cause of dementia in people over the age of 65. Depressive disorders are instead characterized by sadness, severe enough or persistent enough to interfere with functions, and often by decreased interest or pleasure in activities. These include Major Depressive Disorder (MDD), one of the most prevalent and debilitating psychiatric disorders. The prevalence of depression, which is overall 5-8%, is estimated to be 15% among people above 65 years of age. However, in AD, the frequency is around 50%, with a prevalence of major depression in about 14.8% of patients. AD and depression, at times in the form of MDD, are often co-morbidities. On the one hand, depression predisposes to medical illnesses and advances biological aging indicated by shorter telomere length, accelerated brain and advanced epigenetic aging. In this sense, depression may represent a risk factor for AD development, even when it occurs earlier in life. On the other hand, medical illnesses also increase the risk of late-life depression and neurodegenerative diseases often manifested as depressive traits in the early stage. The aim of this work is to show some mechanisms through which chronic inflammation, an early phenomenon linking depression and AD, could predispose depressed patients to neurodegenerative changes later in life, and how this exacerbated inflamed state could be exploited to find new markers for dementia. Mice injected with lipopolysaccharide (LPS) represent a suitable model to study the interaction between MDD and AD, showing memory impairments and depressive-like behaviours. The treatment of these mice with the molecule 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5methyl-1H-1,2,3-triazole-4-carboxamide (QTC-4-MeOBnE) prevents these impairments. QTC-4-MeOBnE can act on BACE-1 which is usually upregulated by pro-inflammatory cytokines with consequent β-amyloid plaque deposition, one of the hallmarks of AD. BACE-1’s transcription is governed by C/EBPβ, whose expression is upregulated by C/EBP-inducing cytokines. Moreover, C/EBPβ is strongly involved in neuroinflammation and mediates IL-6 transcription: a positive feedback loop between inflammatory components and C/EBPβ in the brain is established. C/EBPβ’s activation can also be promoted by the glycoprotein ApoE4, recognized as the most prevalent genetic risk factor for AD. This evidence opens the way to new diagnostic biomarkers targeting neuroinflammation in pre-dementia stage patients experiencing late-life depression (LLD) or amnestic mild cognitive impairment (aMCI), both strongly associated with an increased risk for AD.