Neurodegeneration and memory impairment

Memory and learning impairment is a hallmark in many neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. However, even these diseases share some features, the time of manifestation and symptons are subtly different. In fact, different brain regions and neuron types might be involved in the pathophysiology of each neurodegenerative disease. Nevertheless, one of the main events leading to memory and learning impairment is the synaptic loss in critical brain regions, such as the hippocampus. In addition, several molecular mechanisms have been identified, mainly in the epigenetics field. This findings might contribute to address thouroughly the symptoms and develop specific treatments.

Cognitive decline is a characteristic feature of most neurodegenerative diseases of the central nervous system (1). Yet, cognitive failure manifests with distinct severity levels in different syndromes of cognitive failure (2). In fact, Alzheimer’s Disease (AD) characteristically produces a remarkably pure impairment of declarative memory in its earliest stages (2), while Parkinson’s Disease shows increased susceptibility for mild congnitive impairment and dementia (3). Similarly, other neurodegenerative diseases are strongly associated to cognitive failure and memory and learning impairment, such as Creutzfeld-Jacob disease, frontotemporal dementia and Lewy body disease (2). Because AD and PD mechanisms in memory and learning have been studied in depth, this assay is going to be focused in these two diseases.

In AD, consensus exists that the onset is characterized clinically with memory complaints, which may affect episodic memory, speech production, with naming or semantic problems, or visual orientation (4). In addition, AD patients typically develop a retrograde amnesia, which is the inability to retrieve memories acquired before the onset of the disorder (5). Many studies have shown that the median temporal lobe, which includes the main centers of memory storage and consolidation (i.e. the hippocampus, nucleus basalis and enthorinal cortex), is strongly affected; namely, several patients show reduced volume of grey mater (5). Indeed, this might be due to the proressive and substantial neuronal cell death in these vulnerable brain regions (5,6). This is in consonance with the decrease in synaptic density in association cortices and hippocampus, previous to neuronal demise (2).

On the other hand, although PD is characterized by impaired motor functions, patients with PD experience a wide range of non-motor symptoms, the most important being cognitive impairments that in many circumstances lead to dementia (7). Memory and learning impairment in PD is a single manifestation within the cognitive profile of PD’s dementia (PD-D), involving impairment in planning, abstract thinking, mental flexibility and apathy. These features are observed in early stages of PD as a mild cognitive decline (3). As reported in different studies, several subtypes of memory are affected in PD; namely, episodic memory (7), verbal memory (8), working memory (9) and short-term memory (10) among others. There is evidence that the progression of Lewy bodies, the main pathophysiological element in PD, from subcortical to limbic to cortical areas seems to be the major driving force for development of dementia (7).

Neurodegenerative diseases usually include a variety of pathological patterns and different affected brain regions and neurons (11). Neverthless, AD and PD show classical pathological features of aggregates of insoluble amyloid beta-protein and neurofibrillary tangles consisting of precipitates or aggregates of hyperphosphorylated tau protein. Indeed, AD and PD have much overlap in the development of neurodegeneration. For instance, a significant loss of noradrergenic neurons in the locus coeruleus (LC) has been observed both in AD and PD. The LC innervates the many forebrain regions including the cortex and hippocampus. loss of LC noradrenergic neurons may occur early in the progression o AD, while loss of noradrenergic neurons of LC has been observed in postmorten examinations in PD subjects (12).

Nevertheless, cognitive impairment correlates strongly with synapse loss in the neocortex and hippocampus, which play a critical role in learning and memory. A great deal of evidence supports that soluble Aß oligomers contribute to synapse dysfunction and loss by acting on multiple synaptic receptors including NMDA-type glutamate and α7-nicotinic acetylcholine receptors (6). NMDA in the hippocampus are required for long-term potentiation and synaptic plasticity, which ultimately contributes to memory encoding (13). Several studies have shown that soluble oligomers of Aß or α-sinuclein inhibit LTP and induce progressive spine loss via downregulation of NMDA receptors, followed by synaptic removal of AMPA receptors (6,14). Thus, taken together, oligomer-mediated LTP inhibition, LTD enhancement and synapse loss appear to underlie cognitive impairment in AD and PD.

Last but not least, epigenetic changes have been shown to play an important role in memory and learning dysfuntion in neurodegenerative diseases. Namely, cognitive capacities are constraint by HDAC2-mediated epigenetic blockade. Apparently, HDAC2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concominant decrease in expression and synaptic plasticity (1,15). Similarly, defective miRNA biogenesis, precisely miR-183/96/182 clusters, are associated with a memory decline (16). In pursuit of a treatment, these mechanisms have been countered, and memory impairment has been succesfully reversed in vivo (15,16).

All in all, both spine synapses and neuronal cell demise are thought to contribute to memory and learning impairment in neurodegenerative diseases. The underlying molecular mechanisms are thought to alter a myriad of intracellular metabolic processes and expression patterns. Therefore, it is important to understand the complexity of processes contributing to cognitive decline in neurodegenerative diseases.

References

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[2] Walsh DM, Selkoe DJ. Deciphering the Molecular Basis of Memory Failure in Alzheimer’s Disease. Neuron. 2004 Sept 30; 44: 181-193.

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[10] Degos B, Ameqrane I, Rivaud-Pechoux S, Pouget P, Missal M. Short Term Temporal Memory in Idiopathic and Parkin Associated Parkinson’s Disease. Scientific Reports. 2018 Apr 27. 8: 7637-7646.

[11] Tan SH, Karri V, Wuen Rong Tay N, Hui Chang K, Yen Ah H, Qi Ng P. Emerging Pathways to Neurodegeneration: Dissecting the Critical Molecular Mechanisms in Alzheimer’s disease, Parkinson’s Disease. Biomedicine and Pharmacology. 2018 Dec 13; 111: 765-777.

[12] Xie A, Gao J, Xu L, Meng D. Shared Mechanisms of Neurodegeneration in Alzheimer’s Disease and Parkinson’s Disease. BioMed Research International. 2014 Febr 8; 2014: 8.

[13] Kaldel ER, Dudai Y, Mayford MR. The Molecular and Systems Biology of Memory. Cell, 2014 Mar 27; 157(1):163-186.

[14] Durante V, de Lure A, Loffredo V, Vaikath N, De Risi M, Paciotti M. Alpha-synuclein Targets GluN2A NMDA Receptor Subunit Causing Striatal Synaptic Dysfunction and Visuospatial Memory Alteration. Brain: A Journal od Neurobiology. 2018 Apr 30; 0: 1-21.

[15] Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J. HDAC2 Negatively Regulates Memory Formation and synaptic Plasticity. Natura. 20009 May 7; 459(7243): 55-60.

[16] Jawaid A, Woldemichael BT, Kremer EA, Laferriere F, Gaur N, Afroz T et al. Memory decline and its Reversal in Aging and Neurodegeneration Involve miR-183/96/182 Biogenesis. Molecular Neurobiology. 2018 Aug 9; 56: 3451–3462.

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