Retina and optic nerve are sites of extra-cerebral manifestations of Alzheimer’s Disease (AD). Amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein are detected in eyes from AD patients and transgenic animals in correlation with inflammation, reduction of synapses, visual deficits, loss of retinal cells and nerve fiber. However, neither the pathological relevance of other post-translational tau modifications—such as truncation with generation of toxic fragments—nor the potential neuroprotective action induced by their in vivo clearance have been investigated in the context of AD retinal degeneration. We have recently developed a monoclonal tau antibody (12A12mAb) which selectively targets the neurotoxic 20–22 kDa NH₂-derived peptide generated from pathological truncation at the N-terminal domain of tau without cross-reacting with its full-length normal protein. Previous studies have shown that 12A12mAb, when intravenously (i.v.)-injected into 6-month-old Tg2576 animals, markedly improves their AD-like, behavioural and neuropathological syndrome. By taking advantage of this well-established tau-directed immunization regimen, we found that 12A12mAb administration also exerts a beneficial action on biochemical, morphological and metabolic parameters (i.e. APP/Aβ processing, tau hyperphosphorylation, neuroinflammation, synaptic proteins, microtubule stability, mitochondria-based energy production, neuronal death) associated with ocular injury in the AD phenotype. These findings prospect translational implications in the AD field by: (1) showing for the first time that cleavage of tau takes part in several pathological changes occurring in vivo in affected retinas and vitreous bodies and that its deleterious effects are successfully antagonized by administration of the specific 12A12mAb; (2) shedding further insights on the tight connections between neurosensory retina and brain, in particular following tau-based immunotherapy. In our view, the parallel response we detected in this preclinical animal model, both in the eye and in the hippocampus, following i.v. 12A12mAb injection opens novel diagnostic and therapeutic avenues for the clinical management of cerebral and extracerebral AD signs in human beings.

Cysteine sulfinic acid decarboxylase catalyzes the last step of taurine biosynthesis in mammals, and belongs to the fold type I superfamily of pyridoxal-5′-phosphate (PLP)-dependent enzymes. Taurine (2-aminoethanesulfonic acid) is the most abundant free amino acid in animal tissues; it is highly present in liver, kidney, muscle, and brain, and plays numerous biological and physiological roles. Despite the importance of taurine in human health, human cysteine sulfinic acid decarboxylase has been poorly characterized at the biochemical level, although its three-dimensional structure has been solved. In the present work, we have recombinantly expressed and purified human cysteine sulfinic acid decarboxylase, and applied a simple spectroscopic direct method based on circular dichroism to measure its enzymatic activity. This method gives a significant advantage in terms of simplicity and reduction of execution time with respect to previously used assays, and will facilitate future studies on the catalytic mechanism of the enzyme. We determined the kinetic constants using L-cysteine sulfinic acid as substrate, and also showed that human cysteine sulfinic acid decarboxylase is capable to catalyze the decarboxylation—besides its natural substrates L-cysteine sulfinic acid and L-cysteic acid—of L-aspartate and L-glutamate, although with much lower efficiency.

Tau-targeted immunotherapy is a promising approach for treatment of Alzheimer’s disease (AD). Beyond cognitive decline, AD features visual deficits consistent with the manifestation of Amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) in the eyes and higher visual centers, both in animal models and affected subjects. We reported that 12A12—a monoclonal cleavage-specific antibody (mAb) which in vivo neutralizes the neurotoxic, N-terminal 20–22 kDa tau fragment(s)–significantly reduces the retinal accumulation in Tg(HuAPP695Swe)2576 mice of both tau and APP/Aβ pathologies correlated with local inflammation and synaptic deterioration. Here, we report the occurrence of N-terminal tau cleavage in the primary visual cortex (V1 area) and the beneficial effect of 12A12mAb treatment on phenotype-associated visuo-spatial deficits in this AD animal model. We found out that non-invasive administration of 12 A12mAb markedly reduced the pathological accumulation of both truncated tau and Aβ in the V1 area, correlated to significant improvement in visual recognition memory performance along with local increase in two direct readouts of cortical synaptic plasticity, including the dendritic spine density and the expression level of activity-regulated cytoskeleton protein Arc/Arg3.1. Translation of these findings to clinical therapeutic interventions could offer an innovative tau-directed opportunity to delay or halt the visual impairments occurring during AD progression

Pain is an unpleasant but necessary sensory experience, which facilitates adaptive behaviours, such as fear. Despite recent advances, the question of how the pain experience influences learning of the fear response is still debated ^1,2 . Genetic disorders rendering patients congenitally unable to feel pain have been described, and are usually explained by defects in peripheral nociceptors ^3-5 . It is not known how growing up without pain affects central emotional and motivational responses to aversive stimuli. The rare autosomal recessive Hereditary Sensory and Autonomic Neuropathy type V (HSAN V) is caused by a mutation in the nerve growth factor (NGF) gene (R100W). HSAN V homozygous patients display a congenital indifference to painful events, with deficits in peripheral nociceptors but without overt cognitive impairment ⁶ . In contrast, heterozygous carriers do not present with pain-related deficits and have been identified only through pedigree and genetic screening ^7,8 . We exploited this clinically silent population to dissociate nociceptive from affective features of pain. To address this we investigated both heterozygous knock-in mice bearing the R100W mutation (NGF ^R100W/m mice) and a cohort of HSAN V heterozygous human carriers. Surprisingly, we found that NGF ^R100W/m mice, despite normal responses to a noxious conditioning stimulus, show a deficit in learned fear while their social and innate fear responses are normal. The lack of pain-related fear response was linked to a reduced activation of anterior cingulate and motor cortices and of striatum, but not in primary somatosensory cortex. Likewise, human heterozygous R100W carriers, despite perceiving noxious stimuli and reporting subjective pain thresholds, show increased reaction latencies in response to painful stimulation, alongside a decreased subjective urgency to react. Functional magnetic resonance imaging (fMRI) revealed, comparably to the mouse data, an altered processing of painful stimuli in rostral anterior cingulate, medial premotor cortical regions and striatum. These findings from both human and mouse HSAN V carriers uncover behavioural and motivational consequences of a mild genetic pain insensitivity on the establishment of pain-dependent affective responses and memories.

Complete or partial loss of smell (anosmia), sometimes in association with distorted olfactory perceptions (parosmia), is a common neurological symptom affecting nearly 60% of patients suffering from post-acute neurological sequelae of COronaVIrus Disease of 2019 (COVID-19) syndrome, called long COVID. Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) may gain access from the nasal cavity to the brain (neurotropism), and the olfactory route has been proposed as a peripheral site of virus entry. COVID-19 is a risk factor for developing Alzheimer’s Disease (AD), an age-dependent and progressive neurodegenerative disorder characterized in affected patients by early olfaction dysfunction that precedes signs of cognitive decline associated with neurodegeneration in vulnerable brain regions of their limbic system. Here, we summarize the recent literature data supporting the causal correlation between the persistent olfactory deterioration following SARS-CoV-2 infection and the long-delayed manifestation of AD-like memory impairment. SARS-CoV-2 infection of the olfactory neuroepithelium is likely to trigger a pattern of detrimental events that, directly and/or indirectly, affect the anatomically interconnected hippocampal and cortical areas, thus resulting in tardive clinical dementia. We also delineate future advancement on pharmacological and rehabilitative treatments to improve the olfactory dysfunction in patients recovering even from the acute/mild phase of COVID-19. Collectively, the present review aims at highlighting the physiopathological nexus between COVID-19 anosmia and post-pandemic mental health to favor the development of best-targeted and more effective therapeutic strategies in the fight against the long-term neurological complications associated with SARS-CoV-2 infection.