How we remember — The science behind memory and good health and the Nobel Prize!

There is a big news for all of us to share and rejoice! American Drug Regulator,  FDA,  just a few weeks ago on  June 7, 2021, gave a molecule named Aducunamab an accelerated approval for its use in one of the most devastating disease of the ageing mankind, hallmarked by MEMORY LOSS   or Dementia,  called Alzheimer’s Disease. This epoch making, only the first of its kind in recent years, is likely to provide possible cure to Alzheimer’s disease and therefore may provide much needed solace, not only to pathetic patients in millions world over but also ,as much to their emotionally taxed care givers !

“Memory” is sum and substance of human existence without which no civilisation can either grow or thrive. Even smallest and simplest in the animal kingdom, need memory for their survival and that is what was experimented by Dr Eric Kendel, Founder Director, Centre for neurobiology and behaviour science, university of Columbia, USA, who won coveted Nobel Prize for physiology and medicine in the year 2000 for his unique research work on molecular mechanism of memory creation.

Professor Kandel was born in Vienna. He managed to escape from Vienna (Austria) to USA (New York) at the age of 10 with his parents, forced by Hitler’s vicious attack on Jews. He studied history and literature and not science at Harvard and only later turned to psychiatry and Behavioural Biology. He started looking for molecular basis of thought process and mind. While working in this field, he got interested in exploring molecular basis of ‘Memory’ for which he chose a very simple organism.

Professor Kandel embarked upon studying the nervous system of a simple mollusk, the Sea Slug (Aplysia) which has far fewer nerve cells ~ 20,000 only as against 100 billion in human beings. This mollusk has nerve reflex for protecting its gills, which help in breathing. If they are touched once it closes its gills reflexly using sensory motor reflex arc but if touched time and again, they react less and less. -just as human beings react to unexpected touch many times by habituation. This tolerance or habituation lasts only for minutes to few hours and it suggests “short term memory” . The same stimuli if prolonged and intensified  this sensitization may last for weeks, suggesting that the Sea Slug has developed “long term memory”

Professor Kendel demonstrated that habituation to repeated touching was due to changes in the Synapses (junctional space between the two neurons) .He demonstrated how changes in synapses are central to learning and memory.  Earlier Nobel laureate Dr Paul Greengard of New York (Co recipient of Nobel Prize, 2000) had discovered how neurotransmitters exert their action in the nervous tissue through specific ion channels which releases calcium ions in the nerve terminals which in turn releases more neurotransmitters at the synapses thereby amplifying the reflex. This is due to phosphorylation or adding phosphorus to ion channel proteins.

A more intense and longer lasting stimuli give rise to increased level of cAMP (cyclic AMP) and in turn PKA (protein kinase A is second Messanger) . These signals enter into nerve cell nucleus and prepare proteins. These proteins are also regulated by CERB and APMB proteins which help restructuring synapses resulting in Long Term Memory formation. Therefore, for short term memory there is no formation of proteins and no lasting changes in the structure and function of synapses but only ionic changes whereas in long term memory , there are structural and functional changes in the synapses .Not surprisingly when these protein synthesis were blocked , long term memory were not formed leading to ‘Dementia ‘ as in Alzheimer’s disease.

Such experiments were also carried out later in mice and and other mammals with equal success .

Therefore , it is very clear that repeated and regular practice is key to efficient human memory creation .

Long Term Memory , commonly referred to just as Memory, can be classified into two major types , Explicit or declarative and Implicit or skills & procedural memory .

Explicit memory is related to facts and events ,and are anatomically located in the Medial Temporal lobe , Entro rhinal cortex and Hippocampus  on either halves of the brain . The Implicit memory as mentioned , is skill and procedure based memory which are learned differently and at times even subconsciously without much focused attention unlike explicit memory , which requires full attention.

 Implicit ( skill based) memory generally lasts longer as we realise in our own experience such as cycling or swimming , are skill based memory which are hardly forgotten even without regular practice . Implicit memory has more scattered anatomical locations within the Brain such as , Cerebellum ( the hindmost part of the brain which controls co ordination of movement) , different lobes of Cerebral Cortex and aggregated neuronal groups known as nuclei present below cortical surface such as Amygdala , Caudate nucleus which are interconnected by fast conducting fibres.

‘Dementia ‘ is a word used for forgetfulness. This can be benign forgetfulness of elderly or serious pathological condition such as Alzheimer’s Disease( AD)  , first described by German Neuropathologist named Alois  Alzheimer in 1906 . This is by far the commonest cause of dementia in old age in both sexes and now it is increasing much faster as people live much longer now. Alzheimer’s disease is old age problem though it may be seen in middle aged occasionally and it may run even in families some times.

There are two stages of this disease which are, mild cognitive impairment (MCI) and later full blown Alzheimer’s  disease . MCI which is the early phase of Alzheimer’s disease needs to be distinguished by Benign forgetfulness of normal ageing. Both may have pronounced forgetfulness without losing much of cognitive abilities such as judgement, reasoning and perception . As it advances into Alzheimer’s disease , memory loss becomes severe and language skills, perceptual and motor skills start taking it’s toll.  Frequent Mood changes and even frank depression is quite common in Alzheimer’s disease

There is growing evidence which suggest central toxic role of Amyloid Beta ( AB) and Tau proteins in Alzheimer’s disease, found disproportionately high in extra cellular and intra cellular locations in the brain respectively and doing the damage specially in locations which are known for memory storage, medial Temporal lobe, Enterorhinal cortex and Hippocampus etc  .  The FDA approved aforementioned drug “Aducunamab “ a monoclonal antibody , which removes toxic Amyloid Beta protein from the critical areas of the brain and therefore it is such a futuristic approach to combat the disease process.

Benign Forgetfulness of Ageing ( BFA ) needs to be differentiated from early Alzheimer’s Disease or Mild Cognitive Impairment (MCI ) by three important points.

Firstly MCI start generally later in life and BFA relatively in early years , in fifties or sixties. By the age of 90 almost half of Caucasian population develop Alzheimer’s disease. Secondly , improved imaging has located that in MCI or AD,  it’s the hippocampus and Medial temporal lobe which gets damaged but in BFA it’s the Dentate gyrus,  which is a separate and distinct part of temporal lobe adjacent to Hippocampus . In BFA  , the protein called RbAp 48 is reduced significantly within Dentate gyrus  .

As people age , RbAp 48 level in the neurons specially in Dentate gyrus comes down gradually and this is proportionate to the degree of forgetfulness . If it’s level is restored as in older mice by injecting AbMp 48 into Dentate gyrus , memory function improves significantly even in ageing mice as if it has turned young.

It was later found out that younger blood has more of AbMp 48 and if blood from young mice is transfused to the older mice , it has rejuvenating effect specially in memory function.

There is yet another interesting scientific knowledge and insight into the role of regular exercise and good bone health in promoting memory and retarding the process of ageing. Bone secrets a hormone called ‘Osteocalcin ‘ which acts on all vital organs and regulate it’s functioning. As osteoporosis sets in with the age ,the Osteocalcin level also falls , which significantly reduces AbMp48 level also and therefore , adversely affects memory functions .

Regular exercise improves bone health and increases blood flow leading to improved memory and overall health .

Also, an active mind engaged in intellectual pursuit has been known to improve neuronal plasticity significantly in a number of studies recently by Dr Michael Merzenich  of university of California and Dr Carla Shatz of Stanford university if intellectual activity is supported by physical exercise . It has even been seen to reverse ageing process amazingly fast .

(The author is former Professor and Head of Medicine, RIMS, Jharkhand.)

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