Mechanisms by which autophagy regulates memory capacity in ageing

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Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer's disease models

Abstract Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26–36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20–22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects

Trans-Synaptic Spread of Amyloid-β in Alzheimer’s Disease: Paths to β-Amyloidosis

Neuronal activity has a strong causal role in the production and release of the neurotoxic β-amyloid peptide (Aβ). Because of this close link, gradual accumulation of Aβ into amyloid plaques has been reported in brain areas with intense neuronal activity, including cortical regions that display elevated activation at resting state. However, the link between Aβ and activity is not always linear and recent studies report exceptions to the view of “more activity, more plaques.” Here, we review the literature about the activity-dependent production of Aβ in both human cases and AD models and focus on the evidences that brain regions with elevated convergence of synaptic connections (herein referred to as brain nodes) are particularly vulnerable to Aβ accumulation. Next, we will examine data supporting the hypothesis that, since Aβ is released from synaptic terminals, β-amyloidosis can spread in AD brain by advancing through synaptically connected regions, which makes brain nodes vulnerable to Aβ accumulation. Finally, we consider possible mechanisms that account for β-amyloidosis progression through synaptically linked regions

CREB Regulates Experience-Dependent Spine Formation and Enlargement in Mouse Barrel Cortex

Experience modifies synaptic connectivity through processes that involve dendritic spine rearrangements in neuronal circuits. Although cAMP response element binding protein (CREB) has a key function in spines changes, its role in activity-dependent rearrangements in brain regions of rodents interacting with the surrounding environment has received little attention so far. Here we studied the effects of vibrissae trimming, a widely used model of sensory deprivation-induced cortical plasticity, on processes associated with dendritic spine rearrangements in the barrel cortex of a transgenic mouse model of CREB downregulation (mCREB mice). We found that sensory deprivation through prolonged whisker trimming leads to an increased number of thin spines in the layer V of related barrel cortex (Contra) in wild type but not mCREB mice. In the barrel field controlling spared whiskers (Ipsi), the same trimming protocol results in a CREB-dependent enlargement of dendritic spines. Last, we demonstrated that CREB regulates structural rearrangements of synapses that associate with dynamic changes of dendritic spines. Our findings suggest that CREB plays a key role in dendritic spine dynamics and synaptic circuits rearrangements that account for new brain connectivity in response to changes in the environment

Fmr1-KO mice failure to detect object novelty associates with a post-test decrease of structural and synaptic plasticity upstream of the hippocampus

Abstract Mice with deletion of the FMR1 gene show episodic memory impairments and exhibit dendritic spines and synaptic plasticity defects prevalently identified in non-training conditions. Based on evidence that synaptic changes associated with normal or abnormal memory emerge when mice are cognitively challenged, here we examine whether, and how, fragile entorhinal and hippocampal synapses are remodeled when mice succeed or fail to learn. We trained Fmr1 knockout (KO) and wild-type C57BL/6J (WT) mice in the novel object recognition (NOR) paradigm with 1 h or 24 h training-to-test intervals and then assessed whether varying the time between the presentation of similar and different objects modulates NOR performance and plasticity along the entorhinal cortex-hippocampus axis. At the 1 h-interval, KO mice failed to discriminate the novel object, showed a collapse of spines in the lateral entorhinal cortex (LEC), and of long-term potentiation (LTP) in the lateral perforant path (LPP), but a normal increase in hippocampal spines. At the 24 h, they exhibited intact NOR performance, typical LEC and hippocampal spines, and exaggerated LPP-LTP. Our findings reveal that the inability of mice to detect object novelty primarily stands in their impediment to elaborate, and convey to the hippocampus, sensory/perceptive object representations

Activity-Induced Amyloid-β Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice

Background: A consistent proportion of individuals at risk for Alzheimer's disease show intact cognition regardless of the extensive accumulation of amyloid-β (Aβ) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for Aβ can compensate for the underactivation of Aβ-positive ones to preserve cognition, but the underlying synaptic changes are still unexplored. Methods: Using Golgi staining, we investigate how dendritic spines rearrange following contextual fear conditioning (CFC) in the hippocampus and amygdala of presymptomatic Tg2576 mice, a genetic model for Aβ accumulation. A molecular biology approach combined with intrahippocampal injection of a γ-secretase inhibitor evaluates the impact of Aβ fluctuations on spine rearrangements. Results: Encoding of CFC increases Aβ oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of Aβ oligomers predicts vulnerability to network dysfunctions, as low c-Fos activation and spine maturation are detected in the hippocampus of Tg2576 mice upon recall of CFC memory. Rather, enhanced c-Fos activation and new spines are evident in the amygdala of Tg2576 mice compared with wild-type control mice. Preventing Aβ increase in the hippocampus of Tg2576 mice restores CFC-associated spine changes to wild-type levels in both the hippocampus and amygdala. Conclusions: Our study provides the first evidence of neural compensation consisting of enhanced synaptic activity in brain regions spared by Aβ load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors Aβ oligomerization in the hippocampus and prevents synaptic rearrangements in this region

Immunotherapy with Cleavage-Specific 12A12mAb Reduces the Tau Cleavage in Visual Cortex and Improves Visuo-Spatial Recognition Memory in Tg2576 AD Mouse Model

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 progressio

Lamotrigine rescues neuronal alterations and prevents seizure-induced memory decline in an Alzheimer's disease mouse model

Epilepsy is a comorbidity associated with Alzheimer's disease (AD), often starting many years earlier than memory decline. Investigating this association in the early pre-symptomatic stages of AD can unveil new mechanisms of the pathology as well as guide the use of antiepileptic drugs to prevent or delay hyperexcitability-related pathological effects of AD. We investigated the impact of repeated seizures on hippocampal memory and amyloid-β (Aβ) load in pre-symptomatic Tg2576 mice, a transgenic model of AD. Seizure induction caused memory deficits and an increase in oligomeric Aβ42 and fibrillary species selectively in pre-symptomatic transgenic mice, and not in their wildtype littermates. Electrophysiological patch-clamp recordings in ex vivo CA1 pyramidal neurons and immunoblots were carried out to investigate the neuronal alterations associated with the behavioral outcomes of Tg2576 mice. CA1 pyramidal neurons exhibited increased intrinsic excitability and lower hyperpolarization-activated Ih current. CA1 also displayed lower expression of the hyperpolarization-activated cyclic nucleotide-gated HCN1 subunit, a protein already identified as downregulated in the AD human proteome. The antiepileptic drug lamotrigine restored electrophysiological alterations and prevented both memory deficits and the increase in extracellular Aβ induced by seizures. Thus our study provides evidence of pre-symptomatic hippocampal neuronal alterations leading to hyperexcitability and associated with both higher susceptibility to seizures and to AD-specific seizure-induced memory impairment. Our findings also provide a basis for the use of the antiepileptic drug lamotrigine as a way to counteract acceleration of AD induced by seizures in the early phases of the pathology

Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole

Compulsive symptoms develop in patients exposed to pramipexole (PPX), a dopaminergic agonist with high selectivity for the D3 receptor. Consistently, we demonstrated that PPX produces an exaggerated increase in contrafreeloading (CFL) for water, a repetitive and highly inflexible behavior that models core aspects of compulsive disorders