Noradrenergic Modulation of the Piriform Cortex: A Possible Avenue for Understanding Pre-Clinical Alzheimer’s Disease Pathogenesis

Abstract

Olfactory dysfunction is one of the biomarkers for Alzheimer’s disease (AD) diagnosis and progression. Deficits with odor identification and discrimination are common symptoms of pre-clinical AD, preceding severe memory disorder observed in advanced stages. As a result, understanding mechanisms of olfactory impairment is a major focus in both human studies and animal models of AD. Pretangle tau, a precursor to tau tangles, is first observed in the locus coeruleus (LC). In a recent animal model, LC pretangle tau leads to LC fiber degeneration in the piriform cortex (PC), a cortical area associated with olfactory dysfunction in both human AD and rodent models. Here, we review the role of LC-sourced NE in modulation of PC activity and suggest mechanisms by which pretangle tau-mediated LC dysfunction may impact olfactory processing in preclinical stage of AD. Understanding mechanisms of early olfactory impairment in AD may provide a critical window for detection and intervention of disease progression.

Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration

“…The primary physiological effect of the piriform cortex consists of odor recognition, association, and memory. This is in line with the occurrence of olfactory dysfunction in neurodegeneration, leading to the testing of olfactory activity during early AD for early diagnosis and monitoring subsequent steps in disease progression [74]. Similar findings are obtained in PD [124].…”

“…In fact, the hippocampus features an increase in alpha-syn, and a similar effect is observed within the piriform cortex, mostly within the deep cortical layers. Remarkably, the piriform cortex is growingly recognized to be a primary site of neurodegeneration in dementia, and it is affected at the early stages of neurodegeneration when only a mild cognitive impairment is present at the clinical level [ 19 , 74 , 82 , 84 , 121 , 122 , 123 ]. In fact, the early degeneration of the piriform cortex is associated with mild cognitive impairment and odor loss, which is described in the pre-clinical stages of AD and PD [ 53 , 54 , 55 , 80 , 88 , 89 , 90 ].…”

“…In the present manuscript, the piriform cortex was recruited by alpha-syn and p-Tau accumulation at 7 days following the administration of DSP4. A loss of NE within the piriform cortex may lead to the onset of neurodegeneration acting at the pre-clinical level [ 4 , 70 , 73 , 74 ]. The primary physiological effect of the piriform cortex consists of odor recognition, association, and memory.…”

“…In fact, a loss of NE within the limbic system and the piriform cortex leads to a loss of olfactory perception and recognition, the re-arrangements of neural circuitries, and pathological findings, such as p-Tau deposition within neurons of the piriform cortex. This is reminiscent of what occurs in mild cognitive impairment, dementia, and during limbic involvement of PD [ 53 , 54 , 55 , 56 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. This is key when considering that the piriform cortex is early and markedly affected in AD and PD.…”